Developmental Genes and Malformations in the Hypothalamus

Abstract

The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.

Introduction

The hypothalamus is a highly complex brain territory held to regulate homeostasis and multiple visceral and somatic functions, many of them mediated by the pituitary gland (Saper and Lowell, 2014; Placzek et al., 2020). Because of the remarkable structural heterogeneity of the hypothalamus, the detailed organization of its intrinsic circuitry related to the brain functions it controls remains imperfectly known. Recently a new scenario of hypothalamic studies has emerged due to a marked paradigm shift from the outdated columnar model of Herrick (1910) to the updated prosomeric model of Puelles et al. (2012) and Puelles and Rubenstein (2015). The latter offers a basic regionalization of the mammalian hypothalamus into dorsoventral (longitudinal) and anteroposterior (transversal) developmental units, centered on the notion of natural hypothalamo-telencephalic neuromeric units (i.e., conceiving the telencephalon and eye vesicles as expanded zonal derivatives of the alar hypothalamus).

The prosomeric model is uniquely consistent with the multitude of brain developmental gene expression patterns accrued during the last 40 years, which were meaningless within the columnar model. It can explain many neurogenetic, axonal navigational and patterning data, and applies in other vertebrates (Puelles, 1995; Croizier et al., 2014; Domínguez et al., 2014, 2015; Santos-Durán et al., 2015, 2016, 2018; Nieuwenhuys and Puelles, 2016; Gonzalez et al., 2017; Schredelseker and Driever, 2020). Several recent monographs present structural and functional vertebrate neuroanatomy, including that of the human brain, based on the prosomeric model (Watson et al., 2010; Striedter, 2016; ten Donkelaar, 2018, 2020; Schröder et al., 2020; Striedter and Northcutt, 2020). The advantage of the prosomeric model compared to older models is that it is causally oriented and greatly aids the experimental assessment of molecular and genetic causal mechanisms involved in normal or pathologic neural development. It accordingly promises to aid significantly advances in system physiology and clinical physiopathology in the molecular era, though progress in this direction is still preliminary because physiologists and clinicians are still little aware of the mentioned paradigm shift.

Studies in animal models are essential to evaluate mutations in regulatory genes implicated in hypothalamic development potentially related to rare endocrine disorders associated with congenital malformations such as holoprosencephaly, septo-optic-dysplasia, and congenital obesity. Experimental animal studies, together with data of human patients and their families, are allowing the identification of relevant genes implicated in hypothalamic development, to assess the risk and progression of these rare diseases, and to evaluate possible treatments (e.g., new drugs or gene therapy). Diagnosis and treatment are two of the main problems of patients affected by rare diseases whose origin, in a high percentage (estimated up 72%), is due to the unidentified alteration of one or more genes, most of the patients being children (Nguengang Wakap et al., 2020). Genetic and clinical heterogeneity increases the intricacy of rare diseases or disorders.

For instance, holoprosencephaly (cyclopy), a brain malformation with high clinical variability, is not completely deciphered yet, though we know a number of the genes and a variety of mechanisms involved. A 35–50% of cases are due to chromosomal anomalies such as trisomy 13, whereas up to 25% of cases are non-chromosomal and non-syndromic, associated with specific gene mutations (Dubourg et al., 2004, 2018; Petryk et al., 2015). Most of the known altered genes relate to the signaling pathway of Shh, and, to a lesser extent, to the Nodal and Fgf pathways. All of them participate in the development of hypothalamic and other forebrain regions, as well as of craniofacial structures (Arauz et al., 2010; Mercier et al., 2011; reviewed in Roessler et al., 2018). Further studies of these or other molecules involved in hypothalamic development, illuminating the particular consequences of their selective or combined alterations, will help to understand the causes of these diseases with different clinical phenotypes, as well as their aid in early prenatal detection, which would improve genetic counseling.

Before reviewing how the molecular regionalization of the hypothalamus is established, and the consequences of alterations in the function of genes involved in its development, it is necessary to know where the hypothalamus is located, its limits, and relationships with other forebrain structures. Due to the paradigm shift mentioned above, we will see that these are still somewhat controversial topics.

The Hypothalamus in a Historic Perspective: The Columnar Model vs. the Prosomeric Model

For more than a hundred years, the hypothalamus was regarded as the ventralmost part of the diencephalon. The latter lay between the rostral telencephalon and the caudal midbrain along a straight axis. This so-called columnar model was a result of the attempt by Herrick (1910) to extend the longitudinal functional columns of the hindbrain (visceral and somatic motor and sensory domains) into the forebrain on the sole basis of sulcal accidents of the brain ventricular surface (Figure 1A). Herrick mainly documented his columnar conception in numerous studies of adult amphibian brains, but others, notably Kuhlenbeck, subsequently expanded this model to other vertebrate brains, including mammals, and partly to embryos (Kuhlenbeck, 1927, 1973). It has survived with minor changes up to recent times (Swanson, 1992, 2012; Alvarez-Bolado and Swanson, 1996), though it has become progressively obvious to recent researchers investigating embryonic gene expression patterns and functions that a correlation of these with ventricular sulci is meaningless and provides no basis for causal explanations. In the modern columnar model of Swanson (1992, 2012), the hypothalamus explicitly corresponds to the diencephalic basal plate (continuous rostrally with the supposedly basal subpallium and caudally with the midbrain tegmentum). Accordingly, a motor character is implicitly ascribed to it, despite containing the sensory eyes and the optic chiasma (this is one of the many inconsistencies of the columnar model, which it cannot account for; Swanson, 1992, 2012; and elsewhere, simply does not mention this feature; the paradigm shift resolves this issue, like many others).

Figure 1

The columnar authors assume implicitly (without discussion or any supporting data) that the longitudinal axis of the brain enters the telencephalon (Figure 1A; dash blue line). This contrasts with the curved longitudinal axis of His (1893), his sulcus limitans, and subsequent proponents of the prosomeric model, whose forebrain axis is parallel to the cephalic flexure and ends behind the optic chiasma (Figure 1B; Puelles et al., 2012; Puelles and Rubenstein, 2015; Nieuwenhuys and Puelles, 2016; see their Figure 4). The columnar and prosomeric axes are thus orthogonal to each other (part of the paradigm shift). Consequently, we now interpret meaningfully the four traditional diencephalic “longitudinal” columns as caudo-rostrally disposed of transverse diencephalic and hypothalamic segments (pretectum, thalamus, prethalamus, plus a bipartite -terminal and peduncular- hypothalamus (PT, Th, PTh, PHy, THy; Figures 1B, 2A). These units uniformly display their respective alar and basal domains (solving the problem of the “basal” columnar eyes and chiasma, explained as alar elements). They extend from the diencephalic and hypothalamic floor plate to the corresponding roof plate, both of them being true longitudinal landmarks, like the alar-basal boundary (rather than the columnar ventricular sulci; Puelles, 1995; Nieuwenhuys and Puelles, 2016). Note the hypothalamic roof corresponds to the “telencephalic” septocommissural and chorioidal roof since the hemisphere is a hypothalamic caudal alar evagination (the eye vesicles are smaller evaginations restricted to the rostralmost alar hypothalamus). The hypothalamus thus lies as a whole under the telencephalon and rostrally to the reduced diencephalon within the updated prosomeric model (Figure 1B). The crucial difference between the columnar and prosomeric models is the different conception of the longitudinal axis. In one case, it was defined arbitrarily and teleologically (aiming to explain the forebrain functionally as an expanded hindbrain), postulating unwittingly a bifid telencephalic axial end (Herrick, 1910; Swanson, 2012). In the other case, it was based on a modern understanding of fundamental patterning mechanisms linked to early notochordal signals, obtaining an orthogonal hypothalamic end (His, 1893, 1904; Puelles et al., 2012; Puelles and Rubenstein, 2015). This primary axial differential feature necessarily modifies the important secondary notions of the dorsoventral (DV) and anteroposterior (AP) dimensions of the brain (compare Figures 1A,B). Using one or the other set of spatial references (columnar vs. prosomeric) has important differential outcomes when interpreting the effects of the multiple signaling molecules on forebrain regionalization in normal and altered development (see below).

The prosomeric forebrain alar-basal longitudinal boundary roughly overlaps the longitudinal lineal expression of Nkx2.2 along the entire forebrain, now including the midbrain (Figure 1C; Shimamura et al., 1995; Rubenstein et al., 1998; Hauptmann et al., 2002; Domínguez et al., 2011; Puelles et al., 2012, 2020; Nieuwenhuys and Puelles, 2016). The Nkx2.2-positive band extends along the alar-basal boundary (a sign of equilibrium between ongoing floor-caused basal ventralization vs. roof-caused alar dorsalization, a fundamental patterning antagonism) before it can be detected by any other means. It also divides the hypothalamus into alar and basal moieties. If we leave aside the telencephalon, which is entirely alar in this model (another part of the paradigm shift) and derives from the “dorsal” alar hypothalamus, the non-telencephalic hypothalamus comprises the remaining “ventral” alar, basal and floor plate longitudinal (dorsoventral) domains (Figures 1B, 2A; details below).

The rostralmost hypothalamo-telencephalic locus, named recently the acroterminal domain (AT), occupies the rostral midline (Figures 1B,D, 2, 3; AT; Puelles et al., 2012). Classic studies did not distinguish conceptually this domain. It extends, as shown by experimental fate mapping, from the mamillary rostral end of the floor plate to the prospective anterior commissure site, that is, the rostral end of the septocommissural roof plate (Cobos et al., 2001). Like the rest of the hypothalamus, the AT divides into basal and alar subdomains, separated by the rostral midline confluence of the bilateral alar-basal boundaries. Various unique structures develop at this hypothalamic locus, not present elsewhere in the hypothalamus. For instance, the median eminence and the infundibulum/neurohypophysis complex at the basal AT part, and the optic chiasma and preoptic terminal lamina at the alar AT part; the bilateral retinal cups and optic stalks also are alar acroterminal singularities (Figures 1B,C; Puelles et al., 2012; Puelles and Rubenstein, 2015).

Figure 2

Figure 3

The AT clearly relates causally to sequential “prechordal plate” signals (Figure 1), whose nodal mesodermal cellular sources migrate actively from the rostralmost floor neighborhood (in front of the notochord) up to a neighborhood above the rostralmost roof. Note that in the updated prosomeric model the prechordal plate accordingly is not a fixed “plate,” nor represents an axial dimension (i.e., it does not extend rostrally to the notochord, as was classically assumed in the columnar model). Prechordal migrating cells do not induce at the median AT the equivalent of a notochordal floor plate. Instead, the prechordal cell population moves progressively along the prospective AT in a dorsalward progression from the floor to the roof of the neural primordium. The prechordal plate population induces heterochronic specific effects along this course in the basal and alar hypothalamic/telencephalic AT and surrounding less rostral areas. For instance, prechordal signals specify the mamillary body in the basal hypothalamus (García-Calero et al., 2008), but separate the right and left eyes from the primarily median eye field across alar AT (by repressing the eye fate at the midline). Malfunction of this last mechanism leads to cyclopic and/or holoprosencephalic syndromes, depending on the spatiotemporal circumstances; obviously, telencephalic effects and even effects on the nasal organs are caused higher up along the alar plate and above the roof plate. In human embryos, a narrow contact occurs between prechordal cells and the chiasmatic field at the hypothalamic alar level at stage 9 (1–3 somites; Müller and O’Rahilly, 2003).

At the neural plate and early neural tube stages, the rostral end of the notochord first contacts intimately and induces the hypothalamic floor plate, corresponding to the prospective retromamillary and mamillary floor regions. There is no further floor rostral to the mamillary floor because the notochord does not extend in that direction (the notochord forms in rostrocaudal direction, because it is deposited continuously out of the node as the latter dynamic phenomenon moves back towards the tail). The inducing contact of its tip with the hypothalamic floor is lost subsequently due to the rigidity of the notochord and the formation of the cephalic axial flexure caudally to the hypothalamus, apparently caused by differential alar surface growth vs. restricted basal growth of the neural wall (most of the brain derives from the alar plate).

The notochordal induction in the median overlying neuroectoderm of a floor plate differentiation is a general feature occurring throughout the brain and is visualized by expression of the Shh gene in the inducing and induced tissues (e.g., Ericson et al., 1995a,b, 1998). Shh codes for the secreted diffusible inducing protein SHH. Within the ventral forebrain (midbrain, diencephalon, and hypothalamus) diffused notochordal SHH exerts early on its so-called “ventralizing” effect on median ventral cells, specifying them as the prospective floor. This occurs as well in the hindbrain and spinal cord. As a result, the floor plate neuroepithelial cells activate the Shh gene and start secreting themselves the SHH morphogen. This diffuses into the neighboring basal plate zone (possibly even into alar domains). Only within the basal plate of the expanded forebrain (down to the isthmus) is the diffused floor SHH signal strong enough to induce locally Shh expression (expression remains restricted to the floor plate at hindbrain and spinal cord levels). This characterizes differentially the midbrain, diencephalic and hypothalamic basal plates, and converts them into additional sources of “ventralizing” SHH (Figures 1B,D; Puelles and Rubenstein, 2015; note that, later, part of the tuberal basal hypothalamic Shh expression results in repressed by signals coming from the apposed adenohypophysis).

The epichordal location of the entire forebrain (and associated rostral topological position of the mamillary bodies) is accordingly an important novelty emerging in the updated prosomeric model. This has relevant novel implications for interpreting the regionalizing effects of signaling molecules diffusing from various hypothalamic organizing centers, as will be seen below (Puelles et al., 2012; Puelles, 2013, 2017; Puelles and Rubenstein, 2015). Moreover, the prechordal plate, an external rostral signaling center moving dorsalward along the acroterminal region at early embryonic stages, is not located “ventrally” to the prospective hypothalamus and telencephalon as is usually assumed in columnar literature.

The Hypothalamus in the Updated Prosomeric Model

The prosomeric model reveals a shared genoarchitectonic hypothalamic structure in amniotes and anamniotes (Shimogori et al., 2010; Diez-Roux et al., 2011; Moreno et al., 2012; Puelles et al., 2012, 2013; Puelles, 2013; Domínguez et al., 2014; Morales-Delgado et al., 2014; Díaz et al., 2015; Ferran et al., 2015; Puelles and Rubenstein, 2015; Santos-Durán et al., 2015, 2016, 2018; Schredelseker and Driever, 2020). Affaticati et al. (2015) and Yamamoto et al. (2017) largely confirmed this shared molecular pattern in zebrafish but suggested an alternative vision of the preoptic domain. There is also a genoarchitectonically similar hypothalamus in prechordates (Albuixech-Crespo et al., 2017a,b). The rich genoarchitectonic pattern observed finds no explanation or useful application within the outdated columnar model.

Such comparative studies have generated a first molecular map of distinct hypothalamic alar and basal progenitor domains, quickly expanding it with novel data (e.g., Morales-Delgado et al., 2011, 2014; Puelles et al., 2012; Díaz et al., 2015; Ferran et al., 2015). Different progenitor domains display singular combinatorial profiles with dozens of active and repressed transcription factor genes, partly shared (Puelles and Ferran, 2012). These sets of genomically active transcription factors select among distinct regulatory pathways in the genomic network and enable the local matrix cells to regulate differential aspects of proliferation, produce specific classes of fixed or migrating neuronal types, and modulate other local histogenetic peculiarities affecting axonal navigation and synaptogenesis (Nieuwenhuys and Puelles, 2016). Using this progressively enriched molecular map, we can now start to explore the causal mechanisms leading to comparable neuronal derivatives across vertebrates.

The hypothalamus, which includes the neurohypophysis in its basal acroterminal subdomain, is located ventral to the telencephalon and rostral to the diencephalon proper (Figures 1, 2; see Puelles et al., 2012; Puelles and Rubenstein, 2015 for details). It develops from the secondary prosencephalon, the rostralmost region of the brain, which produces jointly hypothalamus, eye vesicles, and telencephalic hemispheres. Recent genoarchitectonic and fate maps do not ascribe the preoptic area (POA) to the hypothalamus, but to the telencephalic subpallium, as was thought initially (His, 1893, 1904; Bulfone et al., 1993; Rubenstein et al., 1998; Puelles et al., 2000, 2004, 2012; Flames et al., 2007; Bardet et al., 2010; Shimogori et al., 2010; Gelman et al., 2011; Medina and Abellán, 2012).

As regards hypothalamic molecular limits with neighboring regions (telencephalon and diencephalon), the Dlx, Arx, and Mash1 gene markers of the telencephalic subpallium (basal ganglia) stop ventrally at the dorsal limit of the alar hypothalamus, where differential markers such as Otp and Sim1 are characteristic. This defines the longitudinal dorsoventral (DV) boundary of the hypothalamus with the telencephalon (Hy-Tel boundary; Figure 2A; Fan et al., 1996; Puelles et al., 2012; note this is more conventional than real since the telencephalon is an evaginated alar hypothalamic derivative emerged in agnathans; a Sim1-expressing part of the alar hypothalamus co-evaginates into the telencephalic vesicle). The transverse hypothalamo-diencephalic boundary lies caudal to the peduncular hypothalamus, coinciding with the caudal end of Otp and Sim1 expression at the alar hypothalamic paraventricular area and the basal periretromamillary area (Di-Hy boundary; Figure 2A; Shimogori et al., 2010; Morales-Delgado et al., 2011; Puelles et al., 2004, 2012). Other alar gene markers such as Rgs4, Lmo4, and Mfap4 corroborate the same limit (Ferran et al., 2015). Expression of Plagl1, Erbb4, and Irx1 in the basal peduncular hypothalamus also stops caudally at the Di-Hy boundary. Moreover, the expression of members of the Dlx gene family in the prethalamus (alar rostral diencephalon) partially stops at the molecular hypothalamo-diencephalic boundary (Puelles et al., 2020).

Note that in the prosomeric model the hypothalamus is separated from the midbrain by the intercalated diencephalon proper (devoid of the hypothalamus), whereas in the columnar model it was assumed without clear-cut evidence that a part of the basal hypothalamus (called “posterior” hypothalamus) extended caudalwards “under” the thalamus to contact the midbrain tegmentum. We now interpret within the prosomeric model this classic columnar bridge region as the diencephalic basal/floor plates or tegmentum.

During early development, the hypothalamic primordium in vertebrates subdivides molecularly along the prosomeric anteroposterior and dorsoventral dimensions, created by the intersection of the new limits several progenitor domains, each characterized by a differential gene expression code (Shimogori et al., 2010; Diez-Roux et al., 2011; Puelles et al., 2012; Domínguez et al., 2015; Ferran et al., 2015; Santos-Durán et al., 2015, 2016, 2018; Schredelseker and Driever, 2020). As mentioned above, the hypothalamus subdivides dorsoventrally into alar, basal, and floor longitudinal fields throughout its length; the dorsalmost alar subregion corresponds to the telencephalic evagination (which is thus by origin entirely alar, irrespective of its subsequent pallio-subpallial subdivision). Also, the hypothalamus subdivides caudorostrally into two transverse neuromeric areas, the caudal peduncular hypothalamus (PHy) and the rostral terminal hypothalamus (THy). Both are continuous dorsally with specific parts of the hemisphere and the telencephalic roof plate (neuromeres are by definition “complete” transverse divisions of the neural tube, extending from floor to roof. PHy and THy represent thus the hypothalamic parts of the complete hypothalamo-telencephalic prosomeres htp1 and htp2 (normally abbreviated hp1, hp2). The whole evaginated telencephalon corresponds to PHy and hp1, whereas the non-evaginated telencephalic POA corresponds to THy and hp2 (Figure 2).

The novel terms “peduncular” and “terminal” hypothalamus (introduced by Puelles et al., 2012) intend to reduce the confusion created by the columnar-to-prosomeric shift in the conceptual paradigm, by referring to features clearly observable in all vertebrates. The massive lateral and medial forebrain bundles of the cerebral peduncle, together with the fornix tract, ostensibly course dorsoventrally through PHy (or hp1) before the cerebral peduncle bends caudalwards into the tegmentum, hence the chosen “peduncular” name for this caudal part of the hypothalamus (Figure 2B; Puelles et al., 2012). The descriptor “terminal” refers to the characteristic topological position of THy at the rostral “terminus” of the neural tube. In the mouse, PHy and THy are characterized by the differential expression of selective molecular markers such as, e.g., Fgf15, Gsc, Nkx6.2, Otx1, and Zic1/5 observed within THy and Erbb4, Irx1/3/5, Lmo4, Mfap4, Plagl1, and Pmch found expressed within PHy, although all of them show differential distributions along the dorsoventral axis. These markers collectively define the intrahypothalamic boundary (Figures 2A, 3A; Ferran et al., 2015), which coincides with the interneuromeric boundary between hp1 and hp2.

The hypothalamus has no rostral neural neighbors since it represents the most rostral part of the neural tube, jointly with its telencephalic derivatives. As a consequence, the lateral walls of the neural tube singularly fuse one into another at the rostral acroterminal area (AT; Puelles et al., 2012; see also Puelles and Rubenstein, 2015). Note the AT also extends into the median part of the POA, where the thin terminal lamina develops. The latter ends dorsally at the anterior commissure, whose bed represents the septo-commissural roof plate domain corresponding to hp2; the rest of the telencephalic median septum and commissures correspond to the roof plate of hp1 (Figure 2A; Puelles et al., 2012). Obeying to the close range relationship of the acroterminal domain with the migrating prechordal cells and their signals, mouse gene markers such as Fgf8/10/18, Otx2, Pomc, Rax, and Six6 are selectively expressed in this rostromedial hypothalamic area, delimiting it from the rest of THy, although with distinct differences along the dorsoventral dimension (Ferran et al., 2015). Though AT was conceived as a special part of hp2 or THy, its distinct molecular profile suggests it might be conceived alternatively as an atypical but still bilaterally symmetric hp3 hypothalamic prosomere; the AT exists already in prechordates (Albuixech-Crespo et al., 2017b).

Placzek and Briscoe (2005), Manning et al. (2006), Fu et al. (2019) and Placzek et al. (2020) misinterpreted in our opinion Shh-expressing cells observed in midsagittal sections at the chicken rostral diencephalic ventral midline as an “anterior floor plate” (no doubt assuming wrongly that Shh is always a floor plate marker). Actually, these median cells correspond to the Shh-expressing basalacroterminal subdomain. Placzek and collaborators (Fu et al., 2019; Placzek et al., 2020) seem to have assimilated this particular notion, but conjecture a mixture of columnar and prosomeric notions in the form of a novel “anisotropic model of basal hypothalamic development.” Why the model should attend only to basal development remains unclear. In general, these authors seem to imagine the whole hypothalamus as represented by its midline. We now know that part of that midline is an authentic notochord-induced floor plate and the rest is acroterminal domain. What happens at the midline does not explain what happens in the rest of the hypothalamic wall.

As mentioned above, the forebrain basal plate generally expresses Shh secondary to floor plate production of sufficient SHH signal (Puelles et al., 1996, 2012). The acroterminal basal Shh-expressing area is conceivably enlarged by added external prechordal signals; notably, in this respect, the DV dimension of the basal AT area is larger than in any other place in the brain. Placzek and collaborators, possibly misguided by the columnar model (whose expectation of an “anterior floor plate” reaching the telencephalon was not fulfilled in any case), were not consistent in their interpretation with the parallel notion that a floor plate only exists were an early contact of median neuroepithelium with the notochord first occurs. This circumstance is absent at the acroterminal domain, and, accordingly, there is no forebrain floor beyond the mamillary area. This is one of the reasons making the “acroterminal” concept necessary.

Let us return now to PHy and THy dorsoventrally subdivided into longitudinal domains. The alar hypothalamus domain subdivides into parallel paraventricular and subparaventricular longitudinal areas, which extend through both PHy and THy, as repeatedly observed in several vertebrates (Moreno et al., 2012; Puelles et al., 2012; Domínguez et al., 2013; Ferran et al., 2015; Santos-Durán et al., 2016). The paraventricular area (Pa) is the dorsalmost hypothalamic alar longitudinal domain, being significantly broader dorsoventrally in PHy than in THy (where it contacts with the telencephalic POA). The Pa area is an Otp/Sim1-positive and Dlx/Arx-negative domain whose neurons are mostly glutamatergic and produce a series of peptidergic products (Puelles and Rubenstein, 2003; Puelles et al., 2004, 2012; Shimogori et al., 2010; Morales-Delgado et al., 2011; Puelles et al., 2004; Díaz et al., 2015). Neurons produced in this large bi-neuromeric area (hp1 and hp2) are known to project via a compact dorsoventral tract along the transverse AT/THy border into the median eminence and the neurohypophysis, establishing the classic supraopto(preopto)-hypophyseal pathway (note some classic authors included the Pa area in the POA, then thought to be hypothalamic). Rgs4 is restricted to peduncular Pa whereas Fgf15 characterizes mainly terminal Pa (Ferran et al., 2015).

The subparaventricular area (SPa) lies underneath the Pa and is considerably broader dorsoventrally at the THy than at the PHy. SPa expresses Dlx, Arx, Isl1, Vax1, and Gad67, and their neurons are mainly GABAergic (Pa; SPa; Figure 3B; e.g., Puelles et al., 2012). Its acroterminal end expresses selectively Six6 and Six3 (López-Ríos et al., 2003; Conte et al., 2005), among other markers, and produces a singular paramedian neuronal aggregate, the suprachiasmatic nucleus (Puelles and Rubenstein, 2015), know to represent the central circadian clock mechanism (Gillette and Tischkau, 1999; Herzog et al., 2017). The retina and optic stalk area represent evaginated derivatives of the SPa extension into AT, which also appears associated with the optic chiasma (Puelles and Rubenstein, 2015).

In the vertebrate basal hypothalamus, widespread Shh and Nkx2.1 gene markers characterize its ventricular zone and mantle layer, respectively. This pattern occurs across most basal PHy and THy, excepting secondary lack of Shh expression at part of the THy tuberal area and absence of Nkx2.1 at the retromamillary area (Puelles et al., 2012). Other molecular markers are restricted to distinct rostrocaudal prosomeres (PHy, THy, AT) and their dorsoventral basal subdivisions (Figure 3B; Moreno et al., 2012; Puelles et al., 2012; Domínguez et al., 2014, 2015; Ferran et al., 2015; Santos-Durán et al., 2015, 2018; Gonzalez et al., 2017; Schredelseker and Driever, 2020). We distinguish across the bi-neuromeric basal hypothalamus three dorsoventral (longitudinal) domains, a dorsal tuberal/retrotuberal area (Tu/RTu), an intermediate perimamillary/periretromamillary area (PM/PRM), and a ventral mamillary/retromamillaryarea (M/RM; Figure 3). The pairs of entity names refer respectively to correlative THy vs. PHy components (e.g., the tuberal area, Tu, is the terminal basal element that corresponds with the peduncular retrotuberal area, RTu). In general, the terminal Tu and M basal areas are larger than the peduncular RTu and RM ones, while the peduncular PRM area is larger than the terminal PM area (these anteroposterior -AP- differences may be prechordal or AT effects).

The relatively dorsal basal Tu + RTu territory further subdivides dorsoventrally into dorsal, intermediate, and ventral microzonal subdomains, possibly implying analogous DV partitions at the corresponding AT basal domain. This phase of DV regionalization thus defines several tuberal and retrotuberal subareas (TuD, TuI, TuV subareas in basal terminal Tu, and analogous but smaller and less obvious RTuD, RTuI and RTuV subareas in basal peduncular RTu; Figure 3; Puelles et al., 2012; Ferran et al., 2015). We need all of them to place precisely some of the well-known hypothalamic nuclei. This complex picture is complicated further by the existence of numerous tangential cell migrations, both within the basal plate and between the alar and basal plates (Morales-Delgado et al., 2011, 2014; Puelles et al., 2012; Díaz et al., 2015). In some cases, distinct and even massive composite nuclei are found in the adult at sites that are quite different from the microzones where the respective neurons were born (see the cases of the VM and VPM nuclei in Puelles et al., 2012).

Figure 3B summarizes non-exhaustively characteristic gene markers serving so far to identify these primary and secondary basal subdivisions within the prosomeric model (Figure 3B; Puelles et al., 2012; Ferran et al., 2015). The hypothalamic floor plate underlies the retromamillary and mamillary basal plate areas; it is characterized by the expression of marker genes such as Shh, Ntn1, Lmxb1, Foxa1, and Nr4a2 (Figure 3B; Puelles et al., 2012; Ferran et al., 2015; Allen Developing Mouse Brain Atlas).

Each of the described molecularly delimited progenitor subdivisions of the hypothalamus gradually starts its schedule of neurogenesis and usually develops a radial stratification with periventricular, intermediate (sometimes subdivided), and superficial (subpial) mantle cell strata. That is, the microzones or progenitor domains transform into distinct radial histogenetic areas (fundamental morphogenetic units of Nieuwenhuys and Puelles, 2016). At this stage novel, gene expression patterns may appear, indicating progressive activation of differentiation genes that control the differentiation of the locally derived neuronal types (Puelles et al., 1987, 2004). Intermediate stratum cells particularly of the peduncular hypothalamus (both alar and basal) adopt interstitial dispersed positions among the fibers of the medial forebrain bundle and fornix tract, forming what the field conventionally calls lateral hypothalamus (Nieuwenhuys et al., 1982; Geeraedts et al., 1990a,b; Puelles et al., 2012; Croizier et al., 2014). It is unclear whether THy participates in the lateral hypothalamus. Early-born cells forming the superficial stratum (directly or via tangential migration) constitute adult subthalamic, parasubthalamic, lateral tuberal, tuberal suboptic, supraoptic, and entopeduncular nuclei. Some of these names refer to related tracts, such as the optic tract and/or the lateral forebrain bundle or cerebral peduncle. The subthalamic and parasubthalamic populations tangentially migrate subpially from the RM area into the RTu area (ventrodorsal transposition within the peduncular basal plate). The sub- prefix in these two names refer to the outdated columnar axis so that we must translate their descriptive value in the prosomeric model, understanding these hypothalamic elements are actually placed rostral to the diencephalic thalamus, rather than under it (axial bend at the cephalic flexure). Indeed, the cerebral peduncle covers the subthalamic nucleus just before it turns caudalwards into the diencephalic tegmentum (Figure 2B). Inversely, the THy subopticOtp-expressing and vasopressin/oxytocin secreting neurons (corrected term introduced by Puelles et al., 2012; they were classically known inconsistently as “tuberal supraoptic neurons”) migrate ventralwards into the superficial Tu region from the alar supraoptic nucleus, whose cells share the same molecular profile. Recently, Alvarez-Bolado and collaborators reported another ventrodorsal subpial tangential migration, which translocates Foxb1-expressing cells from the mamillary area into the terminal Pa microzone (Zhao et al., 2008; Alvarez-Bolado and Celio, 2016). The authors described the resulting superficial Parvafox nucleus as part of the “lateral hypothalamus” under the level of the optic tract (suboptic), but it clearly also extends above the optic tract (supraoptic; see Foxb1 expression at the Allen Developing Mouse Brain Atlas). The lateral tuberal nuclei are characteristic of primates and we know nothing about their developmental origin. The superficial hypothalamus hence forms a complex stratum with distinct (migrated or non-migrated) alar and basal components. In any case, the late-born major hypothalamic cell masses develop within the periventricular stratum of the respective histogenetic areas (the classic so-called “medial” nuclei; Puelles et al., 2012).

Figure 3C illustrates representative hypothalamic nuclei derived from the described histogenetic subregions (see Puelles et al., 2012 for a more detailed stratification). Briefly, the PHy originates major hypothalamic alar structures such as the dorsoventrally subdivided (dorsal, central, ventral) paraventricular nucleus and the ventral entopeduncular nucleus (DPa, CPa, VPa/LPa, EPV), as well as the basal retromamillary area with its migrated subthalamic and parasubthalamic nuclei (RM, STh/PSTh). Non-acroterminal THy instead gives rise to the supraoptic and anterior alar hypothalamic nuclei (TSO, AH), as well as to the enlarged tuberal and mamillary regions that comprise ventromedial, dorsomedial, and medial/lateral mamillary nuclei (VMH, DMP/DMT, MM/LM) as major basal neuronal formations. The acroterminal domain generates its series of specialized alar and basal nuclei or cell populations, some of which migrate dorsoventrally into the acroterminal arcuate nucleus (Morales-Delgado et al., 2011, 2014; Díaz et al., 2015). The optic stalk, the optic chiasm, and the lateral chiasmatic and suprachiasmatic nuclei derive from the AT subparaventricular alar plate whereas the anterobasal, tuberal-suboptic and arcuate nuclei, as well as the median eminence and infundibulum with the neurohypophysis are AT basal derivatives (os, ch, LCh, SCh, TuSbO, Ar, ME, NHy; Puelles et al., 2012).

In humans, morphological and molecular studies on hypothalamic development are scarce. The best classic source is the atlas of the human brain development of Hochstetter (1919, 1923, 1929). Gilbert (1935), a pupil of Papez, published a detailed analysis of the early development of the human diencephalon, including descriptions of the hypothalamus. This study shows coronal and sagittal sections, presenting sagittal view schemata of landmark tracts correlated with neural populations. These schemata allow us to make a rough neuromeric interpretation of her excellent material (Figure 4; see also Papez, 1940, who elaborated specifically on the hypothalamus). Kuhlenbeck and collaborators also studied between the 19-thirties and fifties the mammalian diencephalon, including the human hypothalamus, using a variant version of the columnar model (Kuhlenbeck and Haymaker, 1949; Kuhlenbeck, 1954, 1973; Christ, 1969). Kuhlenbeck supported the modernly refuted notion of Spatz (1925) that the globus pallidus originates in the hypothalamus and singularly interpreted most of the hypothalamus as an alar plate derivative (i.e., held that the basal plate ends at the mamillary bodies, all the rest being alar; this also has been refuted recently). These other works do not surpass Gilbert’s (1935) report in precision.

Figure 4

Altman and Bayer (1986, 1995) illustrated relevant hypothalamic rat embryonic cell birthday data in high-quality histological material, but interpreted it in a personal variant of the columnar model jointly with many preconceived notions, leading to controversial conclusions. Puelles (1996) reviewed critically some results of this approach. The same authors recently produced a developmental atlas of the human brain in several volumes, which is again worth perusing for its excellent histologic quality, but readers might prefer to eschew odd columnar interpretations of the authors (Bayer and Altman, 2007).

There is otherwise various data on the developing human hypothalamus in Müller and O’Rahilly (1988, 1989a,b, 1990a,b) and O’Rahilly and Müller (1999) or the adult and embryonic primate hypothalamus in Bleier (1984); see Figure 5 and Gribnau and Geijsberts (1985). More recently, Koutcherov et al. (2003) analyzed chemoarchitectonically the developing human hypothalamus through fetal and postnatal stages in coronal sections. These authors offered a classical columnar interpretation of hypothalamic structure, simply dividing it into midline (periventricular), core, and lateral (superficial) zones.

Figure 5

Morphogenetic Organizer Centers of the Hypothalamus

Like the rest of developing brain regions, the prospective forebrain containing the future hypothalamus is under the influence of multiple diffusible signaling molecules produced by extraneural (primary) and neural (secondary) organizers (reviewed in Echevarría et al., 2003; Vieira et al., 2010; Anderson and Stern, 2016; Puelles, 2017). These provide inductive (instructive, repressive) or positional signals which contribute to progressive regionalization, defining more precisely the neural identity or molecular profile of the diverse territories that fall within the range of these organizer systems. Their joint action triggers finer dorsoventral and anteroposterior regionalization in specific neuroepithelial progenitor subdomains. In general, the primary organizers are the main inducers of neural character or fate, a mechanism thought to occur by repression of previously inbuilt ectodermal specification as epidermis (Holley et al., 1995; Wilson and Hemmati-Brivanlou, 1995; De Robertis and Sasai, 1996). Primary neural induction is largely “vertical” since it involves signals coming from a different embryonic layer, i.e., axial mesoderm or endoderm, which act upon the ectoderm (reviewed in Doniach, 1993; Ruiz i Altaba, 1994; Echevarría et al., 2003; Vieira et al., 2010). Contrarily, secondary organizers develop as specializations of the early neuroepithelium, and their signals act mainly by diffusion or propagation by cell-cell contact in the plane of the neural wall (i.e., “planar” effects). Secondary organizers are largely responsible for brain wall differential regionalization (progressive subdivision and delimitation into differentiated smaller neuroepithelial areas; reviewed in Stern, 2001; Echevarría et al., 2003; Puelles, 2017). Positional information is provided by signaling diffusible morphogen molecules such as Sonic Hedgehog and Fibroblast Growth Factors (SHH, FGFs) are secreted by specific secondary organizers and diffuse gradientally. Nearby portions of the neuroepithelium sensible to these molecules react variously depending on the concentration sensed (different according to the distance from the morphogen source), essentially triggering selectively one of the various genetic signalings cascades possible at each locus (Wolpert, 1969, 2016; Gurdon and Bourillot, 2001; Cohen et al., 2013). The newly activated genes modulate the function of pre-existing regulatory genes such as transcription factors or induce the expression of new ones, including differentiation genes (Shimamura et al., 1995; Crossley et al., 1996; Martinez et al., 1999; Martínez, 2001; Echevarría et al., 2003; Davidson, 2006; Puelles and Ferran, 2012; Anderson and Stern, 2016).

The effect of different emerging molecular cascades driven by characteristic combinations of transcription factors occurring selectively in given parts of a neural territory leads to its subdivision into as many parts as those that develop a variant molecular profile, with their now distinct boundaries, potencies, and fates (Echevarría et al., 2003). The earliest molecular boundaries formed at neural plate stages are quite dynamic, often adjusting and refining rapidly their relative position and limits over time, due to agonistic or antagonistic interactions with gene products and intercellular signals produced at neighboring areas (Sánchez-Arrones et al., 2009, 2012). However, this dynamism diminishes or disappears once the neural tube closes, so that boundaries thereafter tend to be persistent, and novel ones simply subdivide former larger fields of neuroepithelium into smaller domains. We assume for simplicity that normally all matrix cells contained within a specific molecularly delimited area express the same set of genes, thus allowing for an “areal” collective manifestation of the same properties and effects within the limits of the area. The area possesses a degree of fate specification, or manifests a variable or permanent state of determination; it behaves as a polyclonal unit with shared molecular properties as long as it does not suffer subdivision by further patterning effects. Adult areal units reach a nearly permanent state of determination. This systematic and progressive molecular compartmentation process is known as “regionalization.” The latter is first molecular (genes active or repressed in the neuroepithelial cells, with the corresponding incipient molecular boundaries), and leads to the area carrying distinct developmental potencies. Later the different molecular profiles start to affect differentially via the corresponding genetic cascades both local proliferation and neurogenesis (birth of neurons) and ulterior differentiation, leading eventually to histologically and anatomically visible boundaries and regions of the brain (Puelles and Ferran, 2012; Nieuwenhuys and Puelles, 2016).

This theory can explain how a specific brain nucleus or a set of nuclei form in typical relative positions. Such explanations were not possible in the non-molecular era of neurobiology. First, a neuroepithelial tissue with generic neural properties arises via vertical signaling (primary organizer signals, neural plate, and neural tube). Next, various secondary organizers emerge at specific sites and start to release gradientally their signals. Some vertical signals may continue active. Some antagonistic effects may occur between adjacent areas expressing incompatible molecular profiles, each one tending to annulate or change the borders of the other. This dynamic preliminary neural plate stage leads in the closed neural tube to a provisional and gradually changing equilibrium of brain wall regionalization, creating finer molecularly distinct microzones or progenitor areas. Each set of distinct matrix cells lose many of their initial potencies, becoming finally restricted to producing only given neuronal types, due to the distinct constellation of genes they keep active. Once the resulting neuronal and glial derivatives are set in place and differentiate in the mantle layer, we have the incipient nucleus. Some nuclei, or most complex structures, such as cortical and reticular formations, resulting from the aggregation and functional interaction of mixtures of neuronal types produced in different progenitor areas.

Any alteration of the regionalization process may produce abnormalities in the final functional cellular structure of the brain (missing, quantitatively abnormal, or badly placed sets of neurons), with consequent effects on the emergent functions. The combined effect of signaling molecules from different organizing sources thus progressively divides the neuroepithelial wall into domains and subdomains with differential genetic patterns. This produces the complex neuronal architecture of the mature brain. The causal explanation requires identifying and following the effects of the relevant organizers in normal and pathological conditions. However, the specific organizer effects operating in the prospective hypothalamic territory are so far only sparsely known. We will summarize the somewhat confused state of the literature on this topic (largely due to the shift in morphological models) by commenting on seven apparent sources of diffusible signaling molecules. These represent more or less established candidate morphogenetic organizers acting upon the prospective hypothalamus: (1) the prechordal plate (rostralizing), and (2) the notochord (ventralizing), a primary vertical action organizer; (3) the floor and basal plate (secondary ventralizing), (4) the anterior neural ridge (ANR) or future roof plate (dorsalizing), (5/6) the median alar and basal acroterminal region (secondary rostralizing), and (7) the hypothalamic ventricular organ (Figure 6A).

Figure 6

Prechordal Plate

Fate-mapping and ablation studies suggest that the prechordal plate is an extraneural organizer acting rostrocaudally—AP dimension—upon the rostral forebrain (a moving organizer, since its cells migrate ventrodorsally in front of the AT). It participates dynamically in early AP organization of the prospective hypothalamus and has a substantial role in the bilateral separation of the eye and telencephalon fields (Li et al., 1997; Pera and Kessel, 1997; Shimamura and Rubenstein, 1997; Camus et al., 2000; Kinder et al., 2001; García-Calero et al., 2008; Aoto et al., 2009). At early primitive streak stages (early gastrulation), the prechordal mesodermal cells originate from the anterior end of the node and migrate dorsalward along the overlying median rostral terminal wall of the neural plate (prospective acroterminal region; Figure 6; e.g., Kinder et al., 2001). Later, they reach the rostral end of the neural tube roof plate, where the anterior commissure forms (Figure 6A, dotted arrow). If the entire forebrain is epichordal (i.e., has a floor plate and underlying notochord), as is proposed in the updated prosomeric model, the prechordal cells move ventrodorsally concerning the topology of the closed neural tube (columnar authors wrongly hold that it extends rostralwards under the hypothalamus; Figures 6B,C). In contrast with the DV ventralizing role of the notochord, the advancing prechordal plate cell population exerts over time a series of AP-patterning effects upon all the primary longitudinal zones of the rostralmost forebrain, present at the prospective AT (compare Figures 6B,C; Puelles and Rubenstein, 2015; Puelles, 2017). Alternative columnar interpretations of conjectural prechordal “DV signaling” on prospective hypothalamus are available (Bedont et al., 2015; Figure 1; Xie and Dorsky, 2017; Figure 2).

Along their para-acroterminal migratory route, the signals secreted by the prechordal cells (e.g., SHH, BMP7; Dale et al., 1997, 1999; Manning et al., 2006; García-Calero et al., 2008) would first promote specification of the mamillary body and enlargement of the tuberal hypothalamus, including the infundibulum and neurohypophysis (basal plate effects). Thereafter they contribute to separate formation of right and left eyes from the median eye field (by repressing this fate at the midline), and finally similarly induce the separation of the two telencephalic hemispheres, inducing also the preoptic terminal lamina (alar plate effects). The sequential removal of the prechordal plate at different times during the gastrulation period produces a range of holoprosencephalic phenotypes (García-Calero et al., 2008). Late ablations produce a nearly normal forebrain, while removal of the prechordal plate at the earliest primitive streak stages cause the largest forebrain defects, comprising absence of the basal hypothalamus, cyclopia, and undivided telencephalic hemispheres, similarly to malformations observed in Shh-defective homozygotic mutants (Chiang et al., 1996; García-Calero et al., 2008). Moreover, early removal also causes underdevelopment or complete absence of basal and floor components of the diencephalon and midbrain (García-Calero et al., 2008). This suggests that the signaling range of the prechordal cells includes these prospective territories at the earliest gastrulation stages, in apparently necessary interaction with notochordal signals (smaller distances all around). In the rat, ablation of prechordal cells also generates diverse holoprosencephalic phenotypes apparent at E9 (Aoto et al., 2009); the surgical ablations were performed at a presomitic stage (zero-somite stage; equivalent to E7.75 in mice) apparently between mid to late primitive streak stages. However, the range of mild to severe phenotypes found by these authors was ascribed to heterochronic aspects of prechordal plate formation in littermates (Theiler, 1989; Fujinaga et al., 1992; Downs and Davies, 1993).

Floor Plate

The floor plate is conventionally recognized as a ventralizing secondary organizer formed at the ventral midline of the neural tube at the prospective spinal cord, hindbrain, and “midbrain” territories; note the latter often included what we now interpret as diencephalic and even hypothalamic floor areas (Figure 6B; Placzek et al., 1991; Yamada et al., 1991; Roelink et al., 1994; Sasaki and Hogan, 1994; Ericson et al., 1995a; Hynes et al., 1995). Conventionally, a similar inductive role of the floor plate at forebrain diencephalic and hypothalamic levels is often unrecognized, due to the classic wrong assumption that the notochord, as well as the floor plate, are absent at these territories (Kingsbury, 1930; Ericson et al., 1995a; e.g., Placzek and Briscoe, 2005 place the notochordal rostral end at the interthalamic zona limitans; their Figure 1B). Several studies identify instead, the prechordal SHH source as the earliest ventralizing organizer acting upon the prospective forebrain (Figure 6C; Yamada et al., 1991; Echelard et al., 1993; Shimamura et al., 1994; Dale et al., 1997; Shimamura and Rubenstein, 1997; reviewed in Placzek and Briscoe, 2005; see their Figure 1). The range of this hypothetic effect would include particularly the entire hypothalamus. This is obviously a notion derived from the supposed longitudinal nature of the hypothalamus “column” within the columnar forebrain model, which disregards the axial role of the notochord. Recent molecular and experimental evidence supporting the prosomeric model contradicts this interpretation (e.g., floor and basal Shh, alar-basal Nkx2.2, alar Pax6 expression patterns; Six3 loss of function phenotype described by Lagutin et al., 2003).

The floor plate is the most ventral longitudinal zone of the neural tube, and the prosomeric model explicitly defines it throughout the neural tube. The expression pattern of several genes circumscribed to the forebrain floor plate supports that the floor region ends at the hypothalamic mamillary pouch, coinciding with the primary rostral end of the underlying notochord (Puelles et al., 2012; Puelles and Rubenstein, 2015). The direct inductive apposition between both structures is only transiently visible at very early embryonic stages (Figure 6A; Puelles and Rubenstein, 2015; their Figure 11). Substantial data support that the prosomeric diencephalic and hypothalamic floor plate differentiates as an axial SHH effect produced by the primarynotochordal organizer (Figure 6B; Bovolenta and Dodd, 1991; Placzek et al., 1993, 2000; Ruiz i Altaba et al., 1993; Roelink et al., 1994; Ericson et al., 1995b; Martí et al., 1995; Dale et al., 1999; Placzek and Briscoe, 2005). The hypothalamic floor (as all other forebrain floor portions) activates itself the Shh gene from neural plate stages onward, and homeotically induces subsequently Shh expression at the local hp1 basal plate (Figure 6A; Echelard et al., 1993; Roelink et al., 1994; Ericson et al., 1995a; Shimamura et al., 1995; Placzek and Briscoe, 2005; Aoto et al., 2009). Importantly, only the floor and basal portions of the acroterminal domain (either a part of hp2 or hp3) express primarily Shh. The prechordal plate ventralization hypothesis would wrongly predict the same result at the alar AT, since all the hypothalamus is underlined by the prechordal plate, and what we consider alar AT is held to be floor/basal in the columnar model. Therefore, we consider the retromamillary (hp1) and mamillary (hp2) hypothalamic floor plate (amplified secondarily by the basal plate) as a hypothalamic organizer source of secreted SHH signal which is shared qualitatively by the whole forebrain. This participates in the DV differentiation of the hypothalamic alar and basal plates, as well as in the positioning of the Nkx2.2-positive alar-basal boundary (Figure 1C; Puelles and Rubenstein, 2015).

This does not rule out an early inductive effect of prechordal plate cells on the prospective mesencephalic, diencephalic, and hypothalamic basal plate (García-Calero et al., 2008). The expression of Nkx2.1, a characteristic marker of the basal hypothalamus, was absent following the removal of the prechordal plate in mouse forebrain neural plate explants at 0–1-somite stages (Shimamura and Rubenstein, 1997). However, basal hypothalamic Nkx2.1 expression emerged when extirpations were carried out at later stages, probably because the migratory prechordal cells were no longer in contact with the hypothalamic basal acroterminal region, having advanced to the alar acroterminal region at these stages (Shimamura and Rubenstein, 1997).

A potential summation effect of SHH inductive signals coming from the floor plate, basal plate, and prechordal plate, probably mediated by a particular enhancer of the SHH signaling pathway (Jeong and Epstein, 2003; Lee et al., 2012), is the ventrodorsal expansion of the basal hypothalamus (e.g., Figures 3, 6). This might explain the great expansion of the hypothalamic basal plate compared to neighboring diencephalic tegmental domains.

Anterior Neural Ridge

The ANR is a putative secondary organizing center of the telencephalon and hypothalamus. We refer to the bilateral neuroectodermal ridge that limits rostrally the neural plate (note there is no neural crest at this level). The ANR receives vertical FGF8 and other primary signals from the underlying anterior visceral endoderm, crucial for the development of the telencephalon (Sánchez-Arrones et al., 2012). As an embryonic structure, it is present from early neural plate stages until the closure of the anterior neuropore, when it transforms into the hypothalamo-telencephalic roof plate, but we do not know when it starts releasing morphogens that pattern the rostral forebrain (ANR; Figure 6A). The literature generally identifies the ANR within columnar assumptions as an AP organizer of the rostralmost prosencephalon (Houart et al., 2002; Lagutin et al., 2003; reviewed in Echevarría et al., 2003; Vieira et al., 2010). However, the ANR lies at the border of rostral neuroectoderm with non-neural ectoderm (Eagleson et al., 1995; Shimamura and Rubenstein, 1997; Houart et al., 1998; Sánchez-Arrones et al., 2009, 2012), and its fused neural material later represents the median septo-commissural roof plate, that is the telencephalo-hypothalamic roof plate (Figure 6A; Cobos et al., 2001). Accordingly, it should function from the beginning as a dorsalizingorganizer, like all other roof-plate signaling centers in the neural tube, and the rest of the neural/non-neural border in the neural plate, excluding the neural crest. We accordingly postulate within the prosomeric model that the ANR organizer has a dorsalizing role both at long range relative to the acroterminal domain and neighboring terminal and peduncular hypothalamic regions, and at close range, upon the associated non-evaginated and evaginated parts of the telencephalon (Beccari et al., 2013; Puelles and Rubenstein, 2015; Puelles, 2017, 2019). Indirectly, its dorsalizing effects upon the AT domain (e.g., the latter’s division into alar and basal moieties, or the early neural plate expression domains of Six3 and Hesx1; Lagutin et al., 2003) may modulate its secondary AP patterning effects (see below). Apart of its dorsalizing effects upon the prospective telencephalon and alar hypothalamus it possibly influences as well early on the fate of the eye fields (see Figures 1A, 6C; e.g., Crossley et al., 2001; Xie and Dorsky, 2017). Thus, the ANR effects antagonize the ventralizing SHH signal secreted by the floor plate at the hypothalamic mamillary/retromamillary levels (ANR, M, RM, floor plate organizer; Figure 6B).

The ANR expresses Fgf family members such as Fgf8 and Fgf17 at neural plate stages in mouse and chick embryos (Crossley and Martin, 1995; Shimamura and Rubenstein, 1997; Maruoka et al., 1998; Crossley et al., 2001; Cholfin and Rubenstein, 2007; Sánchez-Arrones et al., 2009; Cajal et al., 2012; Sánchez-Arrones et al., 2012). Various experimental work, including studies on Fgf8 hypomorphs, shows that the ANR has regulatory FGF8-mediated effects on the anterior forebrain (Shimamura and Rubenstein, 1997; Houart et al., 1998; Ye et al., 1998; Heisenberg et al., 1999; Crossley et al., 2001; Fukuchi-Shimogori and Grove, 2001; Storm et al., 2003, 2006; Paek et al., 2009). However only the knockout of both Fgf8 and Fgf17 genes leads to rostral forebrain defects, the phenotype being milder in Fgf17 knockout mice (Garel et al., 2003; Storm et al., 2006; Cholfin and Rubenstein, 2007, 2008).

Acroterminal Domain

The hypothalamus presents along its acroterminal domain (AT) at least two postulated AP dimension organizers (alar and basal AT of Puelles, 2017), possibly set in place under prechordal, anterior visceral endoderm and ANR influence. The alar and basal parts of the AT express genes coding for SHH receptors (e.g., LRP2, Christ et al., 2012), Shh response elements (Gli3, Haddad-Tóvolli et al., 2015), SHH repressors (Tbx2/3, Manning et al., 2006; Pontecorvi et al., 2008), diffusible morphogens of the Fgf and Bmp families (Manning et al., 2006; Ferran et al., 2015; Fu et al., 2017; Placzek et al., 2020). These are differently combined at the alar and basal parts of the acroterminal region, though the accrued data suggest further DV regionalization of the AT; some data commented below suggest distinct acroterminal mamillary and acroterminal tuberal organizers (Figures 6A,B; Ferran et al., 2015; Puelles and Rubenstein, 2015; Puelles, 2017). The anteroposterior (AP) patterning effects are interpreted as affecting the DV dimension of the hypothalamus within the columnar tradition (e.g., Kapsimali et al., 2004). There is also a novel hybrid model proposed by Placzek and collaborators (Fu et al., 2019; Placzek et al., 2020).

Fgf18, which is expressed in the alar acroterminal subdivision (Figure 6A; Ferran et al., 2015) may have a rostralizing role upon the POA (where an SHH-releasing subpallium organizer emerges; Puelles, 2017) and the underlying alar hypothalamus, including potential effects on the prospective eye field within the early AT, and the paraventricular, supraoptic and suprachiasmatic nuclei subsequently. This hypothesis has not been explored so far experimentally.

On the other hand, the entire alar portion and the tuberal basal part of the acroterminal region (i.e., excepting the mamillary subregion) express Six3 from early neural plate stages onwards (Ferran et al., 2015; Yu et al., 2017). This gene was found to have an antagonizing (rostralizing) effect against caudalizing WNT signals found more caudally in the forebrain (Lagutin et al., 2003). Six3 is one of the genes altered in holoprosencephaly (Schell et al., 1996; Solomon et al., 2009). However, it remains unclear how Six3 counteracts WNT signals since it is a transcription factor. One possibility is that it activates secreted frizzled-related peptide (Sfrp) genes, whose secreted products block WNTs attachment to the receptor Frizzled (see below for Lhx5).

Moreover, Haddad-Tóvolli et al. (2015) studied experimentally the role of Gli1, Gli2, and Gli3 as SHH response elements in the patterning of the hypothalamus, using as reference the prosomeric model. They observed that alar hypothalamic and preoptic regions did not require Gli2 or Gli3 genes, but did depend strongly on prechordal SHH and neural-expressed SHH (probably from the local preoptic source). The basal hypothalamus (particularly its acroterminal and terminal parts; THy) depended importantly on early Gli2A activation at E7.0 by exogenous SHH (prechordal and/or notochordal). Lack of this function caused a caudalized phenotype, in which acroterminal-derived structures (median eminence, neurohypophysis) essentially disappeared, whereas tuberal nuclei, such as the ventromedial nucleus and the arcuate nucleus, appeared fused into unpaired masses in place of the corresponding basal AT. This reveals that the formation of the AT itself requires SHH induction mediated by Gli2, probably starting from prechordal plate signals, known to have a selective Shh enhancer (Lee et al., 2012; Sagai et al., 2019). The gene Gli3 only had a role in the development of the mamillary body, influencing its proliferation. The lateral hypothalamus (PHy) depended mainly on a neurally-expressed SHH signal, which at this level probably results from the local floor and basal plate, which both express Shh.

There is no basal AT expression of Six3 at the tubero-mamillary transitional area and the mamillary/retromamillary basal subregions (ventralmost basal plate; Figure 7B). In contrast, Foxb1, Lhx1, Sim1/2, and Lhx5 are selectively expressed early on at the mamillary portion of the AT and neighboring mamillary area, and these genes are required for normal mamillary body development (Wehr et al., 1997; Alvarez-Bolado et al., 2000; Radyushkin et al., 2005; Heide et al., 2015). In zebrafish, Lhx5 inhibits caudalizing Wnt genes by acting upstream of the Wnt antagonists Sfrp1a and Sfrp5 (Peng and Westerfield, 2006), which implies it exerts a rostralizing effect. The distinction between retromamillary and mamillary areas likely results from WNT vs. Lhx5 antagonism (Heide et al., 2015).

Figure 7

The SHH repressor gene Tbx2/3 appears expressed selectively in the chick (Tbx2) and mouse (Tbx3) tuberal region, inciding somewhat into the mamillary area (Manning et al., 2006; Pontecorvi et al., 2008). Its expression depends likewise upon Lhx5 function at the mamillary AT subdomain, and other genes involved at this locus including Foxb1, Lhx1, and Bmps (Heide et al., 2015; Fu et al., 2019). The potential mouse basal acroterminal organizer thus expresses differentially Tbx3, Lhx5, Fgf10, and Fgf8 (Figure 6A; Crossley and Martin, 1995; Rubenstein et al., 1998; Parkinson et al., 2010; Ferran et al., 2015; Fu et al., 2017; Allen Developing Mouse Brain Atlas). Mouse Tbx3 (similarly as Tbx2 in the chick) correlates in expression with the tuberal and tuberomammillary part of median basal AT territory that initially expresses Shh presumably under dual prechordal and floor plate induction, but where this signal is repressed subsequently by adenohypophysial signals and Tbx3-BMP action (Manning et al., 2006). This repression does not eliminate Shh expression next to the alar-basal boundary. The repressed AT and THy basal tuberal area is important for patterning of the tuberal infundibulum, median eminence, arcuate nucleus, and neurohypophysis (Manning et al., 2006; Trowe et al., 2013; Heide et al., 2015; Fu et al., 2019). Finally, FGF8/10 signals diffused caudalwards from the basal acroterminal subdomain probably participate in additional rostralizing anti-WNT effects in the prospective basal hypothalamus, probably mainly at its tuberal/retrotuberal domains. The literature usually attributes confusingly such effects to the more distant FGF8 source at the ANR, whose effects are dorsoventral rather than anteroposterior (see references cited above; Figure 6; compare b and c).

Hypothalamic Ventricular Organ

Finally, the hypothalamic ventricular organ (HVO, or paraventricular organ, HPV) is a linear longitudinal ependymal specialization running across basal PHy and THy (Figure 6A), which is well-known in non-mammalian vertebrates and is not generally described in mammals (but see Puelles et al., 2012). Nowadays its identification is easier even in mammals by the fact that its ependymal cells express intensely Wnt8b at early embryonic stages, as observed at least in the chick and mouse (Garda et al., 2002; Bardet, 2007). Data presented in recent publications suggest that the HVO appears related topographically to different molecularly defined neuronal populations in the surrounding mantle layer across PHy and THy (Puelles et al., 2012; Li et al., 2018; Diniz et al., 2019). WNT8 is one of the diffusible members of the WNT family and is also relevant for thalamic patterning (Puelles and Martinez, 2013). This longitudinal basal organizer appears dorsal to the floor plate and ventral to the alar-basal boundary, coursing parallel to these two landmarks. It lies along the boundary between the major tuberal/retrotuberal areas and the perimamillary/periretromamillary areas (actually it represents the ependyma of the thin ventral Tu/RTu subdomain, where histaminergic neurons are produced; Puelles et al., 2012). This location confers to it an unexplored DV modulating role inside the basal hypothalamus and its tuberal and mamillary specializations, mediated apparently by the WNT8 morphogen (HVO; Figures 6A,B; Puelles et al., 2012; Puelles, 2017).

Alterations of Genes Implicated in Hypothalamic Development Underlie Human Forebrain Congenital Abnormalities

Next, we will focus on some molecules produced by organizers of the prospective hypothalamus whose abnormal nature (mutation) or distribution may underlie anomalies in the development of the human forebrain. Indeed, mutations in signaling molecules (e.g., SHH and FGFs) and transcription factors (e.g., SIX3, SOX2, and SOX3) have been implicated in midline forebrain defects such as septo-optic dysplasia and holoprosencephaly. However, only 25% of holoprosencephalic cases are due to mutations in known genes correlated with holoprosencephaly (e.g., Shh, Fgf8, Six3), leaving 75% of cases with unknown mutations (Dubourg et al., 2004, 2018; Pineda-Alvarez et al., 2010). In septo-optic dysplasia there are few family cases, the majority of cases being sporadic; thus, less than 1% of septo-optic dysplasia patients have mutations in the genes Hesx1, Sox2, Sox3, or Otx2 (Webb and Dattani, 2010). Both rare congenital diseases are heterogeneous genetic and clinical disorders. Septo-optic dysplasia in Europe has an incidence of 1.9–2.5 cases per 10,000 births (Garne et al., 2018), while the prevalence of holoprosencephaly is 1 case in 10,000 births (Leoncini et al., 2008; Kauvar and Muenke, 2010; Yi et al., 2019; see a systematic review in Orioli and Castilla, 2010).

In humans, holoprosencephaly is the most common developmental anomaly of the forebrain and face. It is characterized by a spectrum of abnormalities ranging from extreme malformations displaying a single undivided forebrain, cyclopia, and proboscis formation (alobar holoprosencephaly, sometimes accompanied by complete dorsalization of the entire forebrain, i.e., no basal plate) to mild alterations such as the absence of the corpus callosum, arrhinencephaly and hypotelorism (lobar holoprosencephaly; reviewed in Cohen, 2006; Dubourg et al., 2007). Lack of a forebrain basal plate by complete dorsalization is the pattern observed by García-Calero et al. (2008) in chick embryos whose prechordal plate was removed experimentally. Mutations in developmental genes implicated in the SHH, FGF, or TGF signaling pathways contribute to holoprosencephaly (reviewed extensively in Roessler and Muenke, 2010; Roessler et al., 2018). Environmental factors such as hyperglycemia and exposure to retinoids or ethanol increase the risk of holoprosencephaly, due to their teratogenic effects on prechordal cell migration and their signaling molecules (Blader and Strähle, 1998; Cohen and Shiota, 2002; Aoto et al., 2008; Miller et al., 2010; Hong and Krauss, 2012, 2017; Kietzman et al., 2014; Billington et al., 2015).

Shh/SHH

Shh is one of the main genes altered in holoprosencephaly, SHH-haploinsufficiency being relatively frequent in patients (Roessler et al., 1996; Nanni et al., 1999; Mercier et al., 2011; Dubourg et al., 2016). Mutations in this gene are associated with 17% of holoprosencephalic familial cases and 3.7% of sporadic cases (Cohen, 2006). However, members of the same family carrying identical Shh mutations can display a great variability of mild-to-severe holoprosencephalic phenotypes. As was described previously, the SHH signaling molecule is produced at several organizer centers (notochord, prechordal plate, floor plate, basal plate, POA), some of which act nearly simultaneously, and others at different developmental times, on the whole, forebrain primordium, or on particular areas such as the prospective hypothalamus (Figure 6). Thus, experimental blocking of SHH signaling at different developmental times by exposing chicken embryos to different doses of the steroidal alkaloid cyclopamine generates a range of craniofacial and brain malformations correlated with temporal disruption of various Shh functions (Cordero et al., 2004; Mercier et al., 2013).

Exposure to ethanol at different gestational periods produces defects related to either holoprosencephaly or septo-optic dysplasia (Lipinski and Bushman, 2010; Lipinski et al., 2010; Kietzman et al., 2014). In any case, the most severe malformations occur after early ablation of Shh-expressing prechordal cells, or blockage of signals released from the median prechordal cells (Li et al., 1997; Pera and Kessel, 1997; Wallis and Muenke, 2000; Aoto et al., 2009). The cited experiments reproduce the severe holoprosencephalic phenotype of the Shh-null homozygous mice (Chiang et al., 1996). The more subtle chirurgic ablation of the prechordal cells at successive stages in chick embryos generated variable holoprosencephalic phenotypes, the most severe corresponding to the earliest interventions (see above; García-Calero et al., 2008). Conditional mice were studied that are defective in Shh expression specifically at the whole basal hypothalamus; these still have persisting SHH signal spreading from the notochord and prechordal plate (Zhao et al., 2012; their Figure 2G). These authors showed pituitary, hypothalamic and optic defects, including reduced numbers of hormone-producing cells, a phenotype more compatible with septo-optic dysplasia than with holoprosencephalic malformations (Zhao et al., 2012). In other types of conditional mutants lacking Shh expression in the basal hypothalamus, this forebrain region was altered, though none of these mutants showed distinct holoprosencephalic features (Szabó et al., 2009; Shimogori et al., 2010; Corman et al., 2018). Hamdi-Rozé et al. (2020) blocked rostral (terminal) hypothalamic NOTCH effects in chick and mouse embryos, obtaining local downregulation of hypothalamic Shh and Nkx2.1 expression, and alterations of other tuberal genes. These experimental embryos died shortly thereafter (after E9.5 in Rbpj knockout mice and after E11.5 in Rbpj conditional mouse mutants) so that a more detailed phenotype could not be examined.

Thus, the complexity in the spatiotemporal expression of Shh possibly correlates with the high variability of clinical phenotypes in holoprosencephaly or other forebrain malformations. In the normal development of the mouse, Shh is strongly expressed in the prechordal plate during a short neural plate period (Echelard et al., 1993). An Shh enhancer related specifically to prechordal Shh expression was reported recently (Lee et al., 2012; Sagai et al., 2019). Moreover, neural Shh has a dynamic spatiotemporal expression in the hypothalamic forebrain (Figure 7A). In very young mouse and chick embryos, Shh is first expressed in the floor plate due to the SHH signal diffused from the underlying notochord. Then Shh expression appears at the floor plate and expands to the hypothalamic basal plate (partly due to joint planar floor signals and frontal vertical prechordal plate effects). Basal plate Shh expression is secondarily downregulated at the tuberal area, the corresponding AT portion, and part of the mamillary area by repressive BMP-TBR2 signals; the tuberal area is where the dorsomedial and arcuate nuclei arise (Figure 7A; Manning et al., 2006; Alvarez-Bolado et al., 2012; Alvarez-Bolado, 2020; Trowe et al., 2013; Corman et al., 2018). Interestingly, the dorsomedial and arcuate cell populations, produced from Shh-downregulated areas, are gabaergic, while populations born where basal Shh expression persists are glutamatergic, as is the case of the ventromedial nucleus, the retromamillary area, and the mamillary area itself (Puelles et al., 2012).

Shh expression in the hypothalamus is required for the formation of various hypothalamic nuclei according to analysis in transgenic mice (Szabó et al., 2009; Corman et al., 2018). SHH signal secreted from extraneural and neural sources exerts its influence on target progenitor domains at the basal hypothalamus through transcription factors GLI2-GLI3, which act in a complex manner (Haddad-Tóvolli et al., 2015; Alvarez-Bolado, 2020). Very early activation of GLI1 downstream of the SHH signal activates the characteristic expression of Nkx2.1 in the basal hypothalamus (Ruiz i Altaba, 1998). Double Gli2/Gli3 mouse mutants showed Shh-downregulation in the whole basal hypothalamus (Motoyama et al., 2003). In humans, Gli2 mutations are mostly associated with median maxillary central incisor and hypopituitarism and rarely to classic holoprosencephaly (Dubourg et al., 2016).

Furthermore, a later neural source of SHH appears separately in the prospective POA, the non-evaginated part of subpallium belonging to prosomere hp2 (Figure 7A; Flames et al., 2007; García-Calero et al., 2008; García-López et al., 2008; Bardet et al., 2010; Alvarez-Bolado et al., 2012; Puelles et al., 2016). This Shh-expressing secondary organizer (the subpallium organizer of Puelles, 2017) produces locally mainly preoptic astrocytes, while many Shh-expressing cells leave this area to populate close or distant telencephalic regions differentiating either as neurons (Marin et al., 2000; Gelman et al., 2009; Hirata et al., 2009) or as oligodendrocytes (Nery et al., 2001; Olivier et al., 2001). Note none of these two sets of authors recognized the preoptic locus of Shh expression (compare Bardet et al., 2010).

Summarizing, SHH-related alterations produced by complete or incomplete deletion of SHH sources, or defective production levels from specific extraneural or neural organizers lead to variably severe anomalies, largely shared with human SHH-related malformations with defects in the hypothalamus. More severe abnormalities (lobar holoprosencephaly) relate to insufficient SHH signaling from the prechordal plate, or inefficient response to such signals (possible case of Six3 KO; see below). Moreover, an abnormal lack of SHH diffusion from the Shh-expressing preoptic subarea postulated as a subpallial organizer (Figure 7A; Puelles, 2017), needs to be considered to understand any subpallial anomalies present in holoprosencephaly. This alar Shh-expressing preoptic territory is probably induced by SHH secreted by migratory prechordal cells reaching the prospective POA at relatively late neural tube stages (García-Calero et al., 2008; Bardet et al., 2010).

Six3

Six3 is a transcription factor required to activate the tuberal basal neural Shh expression in the hypothalamus, besides to control directly or indirectly the expression in the forebrain of other regulative genes (e.g., Hesx1; Foxg1, Nkx2.1, Irx3; Lagutin et al., 2003) or activating genes that code diffusible morphogens such as FGF8 (e.g., Geng et al., 2008). In its turn, Shh maintains Six3 expression in the hypothalamus (Geng et al., 2008; Jeong et al., 2008). Mutations in Six3 are responsible for 4% of holoprosencephalic human cases (Dubourg et al., 2007; Domené et al., 2008). This is one of the first “neural” genes, i.e., genes expressed in the neural plate once the cephalic neural induction takes place, without previous expression in the mesendoderm (Oliver et al., 1995; Bovolenta et al., 1998). Hypothalamic Six3 has rostralizing anti-Wnt effects, and lack of Six3 function leads to a significant caudalization of the rostralmost forebrain (Lagutin et al., 2003). The anterior expansion of canonical Wnt signaling in mice embryos deficient in Six3 causes the complete absence of the hypothalamus, eyes, and telencephalon (Lagutin et al., 2003).

At the earliest neural plate stages in the chick, the Six3 expression ends caudally at the prospective isthmic border, thus spreading throughout the whole forebrain, though excluding the floor plate in the dorsoventral dimension (Figure 7B; Sánchez-Arrones et al., 2009; Dutra de Oliveira Melo, 2011). Thereafter, caudal Six3 expression is progressively downregulated (apparently by antagonism with Irx genes), so that its caudal boundary moves progressively rostralwards through the midbrain and diencephalon. Eventually, Six3 remains expressed only within the secondary prosencephalon, that is, the prospective hypothalamus, eye field, and telencephalon, and even appears finally restricted therein mostly to the acroterminal domain (Figure 7B; Oliver et al., 1995; Bovolenta et al., 1998; Lagutin et al., 2003; Conte et al., 2005; Geng et al., 2008; Dutra de Oliveira Melo, 2011). Loss of Six3 function produces essentially forebrain defects rostral to the prethalamus (diencephalon), with the absence of the telencephalon, hypothalamus, eyes, and pituitary gland, as well as the olfactory placodes (Carl et al., 2002; Lagutin et al., 2003), a phenotype similar to severe holoprosencephaly phenotypes in humans (Cohen, 2006; Dubourg et al., 2007). These results also suggest that the potential effects of Six3 upon early expressing territories caudal to the prethalamo-hypothalamic border (down to the isthmic border) are supplied by some other redundant genetic determinants. As mentioned, finally Six3 expression is restricted to the acroterminal domain of the forebrain (i.e., rostromedial preopto-hypothalamic components; Sánchez-Arrones et al., 2009), which is postulated as a hypothalamic secondary organizer (Puelles et al., 2012; Ferran et al., 2015; Puelles, 2017). This progressive restriction of Six3 expression to the acroterminal subdivision (though excluding its mamillary ventral portion), together with the early rostralizing influence of signaling molecules secreted by the migratory prechordal cells, might induce the significant enlargement of the terminal basal hypothalamus (tuberal area) concerning the peduncular basal hypothalamus and more caudal diencephalic basal domains. The dynamic temporospatial pattern of Six3 expression may explain that already a reduction of Six3 levels in Six3 hypomorphic mice (≤50% signal compared to controls), is accompanied by a consequent severe downregulation of Shh in the hypothalamus, giving rise variously to lobar or semilobar holoprosencephalic phenotypes, depending on Six3 dosage (Zhao et al., 2012; Geng et al., 2016). Alobar cases seem to correlate with a severe Foxg1 downregulation mediated directly or indirectly by the decrease in the Six3 signal (Geng et al., 2008, 2016). Foxg1 is expressed essentially in the telencephalon (Shimogori et al., 2010), though it extends slightly into the neighboring alar paraventricular hypothalamus and the upper part of the optic stalk and retina. In conclusion, Six3 or Shh null animals show a severe holoprosencephalic phenotype (with cyclopia), while diminishing variations in Shh and Six3 levels result in septo-optic dysplasia or holoprosencephaly, respectively, with different degrees of severity (Jeong et al., 2008; Geng et al., 2016). These results explain the high clinical heterogeneity of both disorders.

Within the columnar model (e.g., the version of Swanson, 2012), the Six3 lack of function data are difficult or impossible to explain since a simultaneous loss of the ventralmost “column” across the telencephalic-hypothalamic complex (Figure 6B) should have affected only the subpallium (together with the hypothalamus), and not the pallium. Moreover, failing to form the whole hypothalamus, the phenotype should have included significant pattern alterations in the remaining diencephalon. Contrarily, the latter results are normally patterned in the complete absence of its theoretic hypothalamic floor and basal components.

Fgf8/FGF8

A positive feedback loop between Fgf8 and Shh is also essential for normal forebrain specification (Ohkubo et al., 2002; Storm et al., 2006; Okada et al., 2008). The FGF8 protein, encoded by the Fgf8 gene, is a member of the family of fibroblastic growth factors, whose biological activity is mediated by tyrosine kinase membrane receptors. Members of the FGFs family (FGF8; FGF15) secreted by the ANR play an important role in the development of the forebrain (Gimeno et al., 2002; Vieira et al., 2010). Less is known about the effects of FGF8 and FGF10 released by the acroterminal domain. FGF signaling molecules regulate the expression of other genes in various patterning centers (e.g., Shh, Bmp4, and Wnt8b), and also serve non-instructively in the form of concentration gradients as positional references for regionalization of forebrain territories, thus assisting the differentiation of cell fates (Tsai et al., 2011). In the telencephalon, FGF8 secreted from the ANR organizer regulates Six3 expression and the activation of Nkx2.1 in the subpallium. In its turn, NKX2.1 activates Shh expression in the POA (the postulates subpallial organizer; Puelles, 2017), suggesting a synergistic mechanism in telencephalic development (Ohkubo et al., 2002; Geng et al., 2008). Neural Shh interacts with Foxg1, Six3, Fgf8, Bmp4, and Wnt8b for splitting the eye field and the primary unpaired telencephalic field (Geng et al., 2016). A similar interaction of these signaling pathways may be also implicated in the rostralizing patterning of the hypothalamus where most of these molecules are also expressed. In zebrafish, a decrease in both Fgf8 and Fgf3 produces a reduction in Shh expression in the basal hypothalamus (Walshe and Mason, 2003).

The Fgf8 signal appears important in the basal acroterminal hypothalamic area (Ferran et al., 2015), particularly in the mamillary subregion. FGF8 protein spreads caudalwards from the mamillary AT source and probably affects the anteroposterior organization of the prospective mamillary/retromamillary area, and possibly also the neighboring adenohypophysis, which is likewise regionalized into distinct sectors (Figure 6). However, the impact of Fgf8 signaling on hypothalamic development is not well understood yet either in humans or in animal models. The first recessive mutation in the Fgf8 gene appeared in a patient with semilobar holoprosencephaly associated with diabetes insipidus and deficiencies in the pituitary hormones ACTH and TSH (McCabe et al., 2011). Recently, Fgf8 was included among major genes implicated in holoprosencephaly due to its frequency of mutation (2.3%) in a cohort of 257 diagnosed patients, similar to the frequencies of Six3 (2.7%) and Gli2 (3.1%), two other holoprosencephaly-related genes (see above; Dubourg et al., 2016).

The most direct evidence for the implication of Fgf8 signaling in the patterning of the neuroendocrine hypothalamus and the pituitary gland bases on the study of hypomorphic Fgf8 mice with variously decreased levels of Fgf8 expression. Fgf8 hypomorphic homozygous mice (<50% Fgf8 expression compared to wildtype mice) have serious defects in forebrain morphogenesis. They show prosencephalic hypoplasia with the absence of the corpus callosum, optic chiasm, and olfactory bulbs (Meyers et al., 1998; Storm et al., 2003, 2006). The severity of holoprosencephalic defects correlated with the reduction of Fgf8 levels (Storm et al., 2006). Two main phenotypes were described: one severe phenotype shows a great reduction of adenohypophyseal tissue and absence of the posterior pituitary lobe (neurohypophysis), and a less severe phenotype, in which the pituitary gland is about normal. In the latter case, the number of oxytocinergic and vasopressinergic neurons was reduced in the hypothalamic paraventricular, supraoptic, and suprachiasmatic nuclei (Brooks et al., 2010; McCabe et al., 2011). These alterations affecting the alar hypothalamus probably result from a decrease of dorsalizing FG8 released from the ANR, rather than from the rostralizing basal acroterminal organizer (see above; Figure 6). The reduction of hypothalamic peptidergic populations appears thus linked to a decrease in the FGF8 signal. In the alar paraventricular area, the peptidergic differentiation genes are activated downstream of Otp and Sim1, which suggests a direct or indirect action of FGF8 upon the expression of these master genes. Otp and Sim1 are involved in the specification viaBrn2 of peptidergic neurons releasing differentially oxytocin, vasopressin, corticotropin, thyrotropin, and somatostatin in the hypothalamic alar paraventricular domain (Michaud et al., 1998). Other basal peptidergic populations originate from the anterobasal area of the tuberal domain and migrate thereafter into the capsule of the ventromedial nucleus and the arcuate nucleus (Michaud et al., 1998; Acampora et al., 1999; Wang and Lufkin, 2000). FGF8 represses the Otp1 gene in the zebrafish hypothalamus (Del Giacco et al., 2006). As mentioned above, the tuberomammillary sector of the acroterminal area also expresses strongly Fgf8 (Figure 6A; Allen Developing Mouse Brain Atlas) and may be relevant for AP patterning of the Otp/Sim1-expressing perimamillary/periretromamillary basal band, where the dorsal premamillary nucleus develops (Figure 6B, green arrow).

Interestingly, in hypomorphic Fgf8 heterozygous mice with 50% Fgf8 expression, which have no apparent body or brain alterations, anxious behaviors were described, associated with a reduction in certain hypothalamic serotonergic populations (Brooks et al., 2014), associated with the hypothalamic ventricular organ (HVO; Figure 6A). Also, these mutants suffering stress exhibited postnatal alterations in the temporal development of corticotrophin-releasing hormone in the paraventricular hypothalamic nucleus jointly with an increase in serum cortisone levels, which suggests an alteration of the hypothalamus-pituitary-adrenal axis (Rodriguez et al., 2015).

On the other hand, Ericson et al. (1998) demonstrated in mice a requirement for FGF8 released from the hypothalamic acroterminal basal region in the maintenance of cell proliferation at the adenohypophysis viaLhx3. FGF8 is thus needed for the activation of the Lhx3 gene and the consequent development of Rathke’s pouch (Takuma et al., 1998). The prospective adenohypophysis (a midrostral ectodermal derivative; see Sánchez-Arrones et al., 2015) is accordingly under the diffusion range of acroterminal FGF8/FGF10 signaling (Takuma et al., 1998; Ohuchi et al., 2000). However, it has not been determined yet whether the action of both factors, FGF8 and FGF10 overlap, or to what extent each of these factors modulates differentially the morphogenesis of Rathke’s pouch and the pattern of pituitary progenitors formed within it (Osmundsen et al., 2017).

SOX2/SOX3

The transcription factors SOX2 and SOX3 are two dose-dependent regulators of hypothalamic Shh transcription by activation of a specific long-range Shh forebrain enhancer in the mouse (Zhao et al., 2012). These transcription factors are highly expressed in the hypothalamus, including the infundibulum (Wood and Episkopou, 1999; Rizzoti, 2015), and their mutations are linked to septo-optic dysplasia (Kelberman and Dattani, 2006; Sato et al., 2007). Family cases associated with mutations in Sox2 or Sox3 are rarely a cause of this disorder (Webb and Dattani, 2010). This disorder displays alterations in brain development with high phenotypic variability due to the contribution of multiple factors, such as genetic conditions, maternal age, and environmental factors (e.g., alcohol or other drug consumption). Patients show at least two features of the classical triad: hypoplasia of the pituitary gland, unilateral or bilateral hypoplasia in the optic nerve (occasionally with more severe abnormalities such as microphthalmia or anophthalmia), and defects in the forebrain midline (e.g., absence of the septum pellucidum or agenesis of the corpus callosum), combined or not with other defects. Sox2 appears to be more related to anophthalmia/microphthalmia and hypogonadotropic hypogonadism, while Sox3 tends to be associated to abnormalities of the brain midline and hypopituitarism (reviewed in Kelberman et al., 2009; Webb and Dattani, 2010).

Sox3 knockout mice show hypopituitarism and craniofacial defects (see Kelberman et al., 2009 for a review of pituitary genetic disorders; Rizzoti and Lovell-Badge, 2007). Besides, mice with mutations in Sox2 or Sox3, used as animal models of septo-optic dysplasia, display downregulation of Shh expression (Dattani et al., 1998; Dasen and Rosenfeld, 2001; Rizzoti et al., 2004; Kelberman and Dattani, 2006; Zhao et al., 2012). In these mutants, there is an expansion of the expression of members of the Fgf and Bmp families in the basal acroterminal domain, where the neurohypophysis is formed in contact with Rathke’s pouch. Typically, enlargement of Rathke’s pouch occurs, and multiple ectopic adenohypophysial primordia are produced (Zhao et al., 2012). Patients suffering from septo-optic dysplasia often have deficiencies in one or more pituitary hormones (Kelberman and Dattani, 2008). Furthermore, conditional elimination of Shh expression in the mouse basal hypothalamus showed defects consistent with septo-optic dysplasia, similarly as observed in mice embryos lacking Sox3 and heterozygous for Sox2. Interestingly, Sox2 mutants exhibited a higher reduction of Shh and more severe defects in eyes, hypothalamus, and pituitary gland than mutants lacking Sox3. These results suggest that the range of decrease of Shh expression levels in the hypothalamus may correlate with the phenotypic variability exhibited in patients with septo-optic dysplasia (Zhao et al., 2012). SoxB1 function controls the expression of Six6 at the alar suprachiasmatic AT portion (Lee et al., 2012).

Hesx1

A larger proportion of the familiar cases of septo-optic dysplasia present mutations in Hesx1 in homozygosis or heterozygosis (latter type related to milder phenotypes; Dattani et al., 1998; Thomas et al., 2001; Kelberman and Dattani, 2007a,b). There is, however, a low incidence in humans (1% of cases with septo-optic dysplasia, or presence of a single feature of the syndromic triad; McNay et al., 2007). Hesx1 null mice exhibit midline forebrain and eye defects, as well as pituitary dysplasia, highly comparable to human septo-optic dysplasia (Dattani et al., 1998; Andoniadou et al., 2007; Sajedi et al., 2008). Hesx1 is a paired-like homeobox gene with a spatiotemporal dynamic expression, which acts as a transcriptional repressor. However, its targets remain unknown. In the mouse, this gene is expressed first during gastrulation in the anterior visceral endoderm, and later in the prechordal mesoderm and rostromedial forebrain (at neural plate stages). The neural expression domain, descending dorsoventrally into the hypothalamus along with the median acroterminal domain, roughly overlaps that of Six3. Ulteriorly, Hesx1 expression becomes restricted to Rathke’s pouch, and its signal disappears at E13.5 (Hermesz et al., 1996; Thomas and Beddington, 1996). Other genes related to septo-optic dysplasia are Tcf4, Noggin, Wnt5a, and Vax1 (Bertuzzi et al., 1999; Brinkmeier et al., 2007; Davis and Camper, 2007; Potok et al., 2008). SHH released from the prechordal plate regulates the expression of Vax1 and Vax2 in the alar hypothalamus. These are genes implicated in the development of the eye, alar hypothalamus, and prethalamus (Take-uchi et al., 2003; Kim and Lemke, 2006).

Concluding Remarks

In summary, experimental evidence in different animal models, complemented with mutations found in humans related to forebrain and craniofacial defects, show the implication of several signaling molecules (mainly SHH, FGF8, BMPs, possibly also WNT8b) and transcription factors (e.g., GLI1-3, HESX1, SIX3, SOX2, SOX3), in the specification of complex rostral forebrain structure [hypothalamus, eyes, telencephalon; see a recent analysis by Kim et al. (2019) of familiar combinatorial genetic and phenotypic precedents]. These molecules execute their respective roles acting upstream or downstream of spatially distinct signaling pathways able to organize DV or AP patterns, and acting in a parallel or sequential manner. Disruptions of one or more signaling molecules secreted by such organizer sources can generate abnormal development of the forebrain (including the hypothalamus). Mutations or biochemical disturbances caused by environmental factors may alter the functional expression or dosage of both transcription factor genes and/or morphogens, hence underpinning different forebrain disorders showing considerable clinical heterogeneity.

The strict dependency of causal explanations on the accurate morphological assessment of DV vs. AP positions has determined the recent paradigm shift from the classic columnar morphological model to the prosomeric model. The columnar model served conventionally as long as no causal explanation was possible and the field mainly demanded superficial functional analysis. As soon as the molecular era arrived and experimental developmental neurobiology started, it became clear that the outdated columnar model produces misleading and confusing causal interpretations, mainly due to its arbitrary definition of the axial dimension of the forebrain. The shift to the causally more realistic prosomeric model poses no problem for the integration of the advances in functional neurobiology made during the preceding columnar era.

References

• 1

  AcamporaD.PostiglioneM. P.AvantaggiatoV.Di BonitoM.VaccarinoF. M.MichaudJ.et al. (1999). Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene. Genes Dev.13, 2787–2800. 10.1101/gad.13.21.2787

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AffaticatiP.YamamotoK.RizziB.BureauC.PeyriérasN.PasqualiniC.et al. (2015). Identification of the optic recess region as a morphogenetic entity in the zebrafish forebrain. Sci. Rep.5:8738. 10.1038/srep08738

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  Albuixech-CrespoB.Herrera-ÚbedaC.MarfanyG.IrimiaM.Garcia-FernàndezJ. (2017a). Origin and evolution of the chordate central nervous system: insights from amphioxus genoarchitecture. Int. J. Dev. Biol.61, 655–664. 10.1387/ijdb.170258jg

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Albuixech-CrespoB.López-BlanchL.BurgueraD.MaesoI.Sánchez-ArronesL.Moreno-BravoJ. A.et al. (2017b). Molecular regionalization of the developing amphioxus neural tube challenges major partitions of the vertebrate brain. PLoS Biol.15:e2001573. 10.1371/journal.pbio.2001573

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AltmanJ.BayerS. A. (1986). The development of the rat hypothalamus. Adv. Anat. Embryol. Cell Biol.111, 1–178.

  • Pubmed Abstract
  • Google Scholar

• 6

  AltmanJ.BayerS. A. (1995). Atlas of Prenatal Rat Brain Development.Boca Raton: CRC Press.

  • Google Scholar

• 7

  Alvarez-BoladoG. (2020). “Sonic hedgehog in Hypothalamus Development,” in Developmental Neuroendocrinology, eds WrayS.BlackshawS. (Switzeland: Springer Nature), 31–66.

  • Google Scholar

• 8

  Alvarez-BoladoG.CelioM. R. (2016). The ventrolateral hypothalamic area and the parvafox nucleus: role in the expression of (positive) emotions?J. Comp. Neurol.524, 1616–1623. 10.1002/cne.23853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  Alvarez-BoladoG.PaulF. A.BlaessS. (2012). Sonic hedgehog lineage in the mouse hypothalamus: from progenitor domains to hypothalamic regions. Neural Dev.7:4. 10.1186/1749-8104-7-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  Alvarez-BoladoG.SwansonL. W. (1996). Developmenrtal Brain Maps: Structure of the Embryonic Rat Brain.London, New York: Elsevier.

  • Google Scholar

• 11

  Alvarez-BoladoG.ZhouX.CecconiF.GrussP. (2000). Expression of Foxb1 reveals two strategies for the formation of nuclei in the developing ventral diencephalon. Dev. Neurosci.22, 197–206. 10.1159/000017442

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  AndersonC.SternC. D. (2016). Organizers in development. Curr. Top. Dev. Biol.117, 435–454. 10.1016/bs.ctdb.2015.11.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  AndoniadouC. L.SignoreM.SajediE.Gaston-MassuetC.KelbermanD.BurnsA. J.et al. (2007). Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development134, 1499–1508. 10.1242/dev.02829

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  AotoK.ShikataY.HigashiyamaD.ShiotaK.MotoyamaJ. (2008). Fetal ethanol exposure activates protein kinase A and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly. Birth Defects Res. A Clin. Mol. Teratol.82, 224–231. 10.1002/bdra.20447

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  AotoK.ShikataY.ImaiH.MatsumaruD.TokunagaT.ShiodaS.et al. (2009). Mouse Shh is required for prechordal plate maintenance during brain and craniofacial morphogenesis. Dev. Biol.327, 106–120. 10.1016/j.ydbio.2008.11.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  ArauzR. F.SolomonB. D.Pineda-AlvarezD. E.GropmanA. L.ParsonsJ. A.RoesslerE.et al. (2010). A hypomorphic allele in the FGF8 gene contributes to holoprosencephaly and is allelic to gonadotropin-releasing hormone deficiency in humans. Mol. Syndromol.1, 59–66. 10.1159/000302285

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  BardetS. M. (2007). Organización Morfológica y Citogenética del Hipotálamo del Pollo Sobre Base de Mapas Moleculares.Universidad de Murcia. Available online at: https://digitum.um.es/digitum/handle/10201/31677.

  • Google Scholar

• 18

  BardetS. M.FerranJ. L.Sanchez-ArronesL.PuellesL. (2010). Ontogenetic expression of sonic hedgehog in the chicken subpallium. Front. Neuroanat.4:28. 10.3389/fnana.2010.00028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  BayerS. A.AltmanJ. (2007). Atlas of Human Central Nervous System Development (Five volume set).London; New York: CRC Press.

  • Google Scholar

• 20

  BeccariL.Marco-FerreresR.BovolentaP. (2013). The logic of gene regulatory networks in early vertebrate forebrain patterning. Mech. Dev.130, 95–111. 10.1016/j.mod.2012.10.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BedontJ. L.NewmanE. A.BlackshawS. (2015). Patterning, specification and differentiation in the developing hypothalamus. Wiley Interdiscip. Rev. Dev. Biol.4, 445–468. 10.1002/wdev.187

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BertuzziS.HindgesR.MuiS. H.O’LearyD. D.LemkeG. (1999). The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain. Genes Dev.13, 3092–3105. 10.1101/gad.13.23.3092

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  BillingtonC. J.SchmidtB.MarcucioR. S.HallgrimssonB.GopalakrishnanR.PetrykA. (2015). Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice. Dis. Model Mech.8, 139–146. 10.1242/dmm.018275

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BladerP.SträhleU. (1998). Ethanol impairs migration of the prechordal plate in the zebrafish embryo. Dev. Biol.201, 185–201. 10.1006/dbio.1998.8995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  BleierR. (1984). The Hypothalamus of the Rhesus Monkey. A Cytoarchitectonic Atlas.Madison, Wisconsin: The University of Wisconsin Press.

  • Google Scholar

• 26

  BovolentaP.DoddJ. (1991). Perturbation of neuronal differentiation and axon guidance in the spinal cord of mouse embryos lacking a floor plate: analysis of Danforth’s short-tail mutation. Development113, 625–639.

  • Pubmed Abstract
  • Google Scholar

• 27

  BovolentaP.MallamaciA.PuellesL.BoncinelliE. (1998). Expression pattern of cSix3, a member of the Six/sine oculis family of transcription factors. Mech. Dev.70, 201–203. 10.1016/s0925-4773(97)00183-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  BrinkmeierM. L.PotokM. A.DavisS. W.CamperS. A. (2007). TCF4 deficiency expands ventral diencephalon signaling and increases induction of pituitary progenitors. Dev. Biol.311, 396–407. 10.1016/j.ydbio.2007.08.046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BrooksL. R.ChungW. C.TsaiP. S. (2010). Abnormal hypothalamic oxytocin system in fibroblast growth factor 8-deficient mice. Endocrine38, 174–180. 10.1007/s12020-010-9366-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  BrooksL. R.EnixC. L.RichS. C.MagnoJ. A.LowryC. A.TsaiP. S. (2014). Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system. Behav. Brain Res.264, 74–81. 10.1016/j.bbr.2014.01.053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  BulfoneA.KimH. J.PuellesL.PorteusM. H.GrippoJ. F.RubensteinJ. L. (1993). The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in midgestation mouse embryos. Mech. Dev.40, 129–140. 10.1016/0925-4773(93)90071-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  CajalM.LawsonK. A.HillB.MoreauA.RaoJ.RossA.et al. (2012). Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo. Development139, 423–436. 10.1242/dev.075499

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  CamusA.DavidsonB. P.BilliardsS.KhooP.Rivera-PérezJ. A.WakamiyaM.et al. (2000). The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo. Development127, 1799–1813.

  • Pubmed Abstract
  • Google Scholar

• 34

  CarlM.LoosliF.WittbrodtJ. (2002). Six3 inactivation reveals its essential role for the formation and patterning of the vertebrate eye. Development129, 4057–4063.

  • Pubmed Abstract
  • Google Scholar

• 35

  ChiangC.LitingtungY.LeeE.YoungK. E.CordenJ. L.WestphalH.et al. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature383, 407–413. 10.1038/383407a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  CholfinJ. A.RubensteinJ. L. (2007). Genetic regulation of prefrontal cortex development and function. Novartis Found. Symp.288, 165–173; discussion 173–167, 276–181.

  • Pubmed Abstract
  • Google Scholar

• 37

  CholfinJ. A.RubensteinJ. L. (2008). Frontal cortex subdivision patterning is coordinately regulated by Fgf8, Fgf17 and Emx2. J. Comp. Neurol.509, 144–155. 10.1002/cne.21709

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  ChristA.ChristaA.KurE.LioubinskiO.BachmannS.WillnowT. E.et al. (2012). LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev. Cell22, 268–278. 10.1016/j.devcel.2011.11.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  ChristJ. F. (1969). “Derivation and boundaries of the hypothalamus, with atlas of hypothalamic grisea,” in The Hypothalamus, eds HaymakerW. A. E.NautaW. J. H. (Springfield, IL: Charles C. Thomas), 13–60.

  • Google Scholar

• 40

  CobosI.ShimamuraK.RubensteinJ. L.MartínezS.PuellesL. (2001). Fate map of the avian anterior forebrain at the four-somite stage, based on the analysis of quail-chick chimeras. Dev. Biol.239, 46–67. 10.1006/dbio.2001.0423

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  CohenM.BriscoeJ.BlassbergR. (2013). Morphogen interpretation: the transcriptional logic of neural tube patterning. Curr. Opin. Genet. Dev.23, 423–428. 10.1016/j.gde.2013.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  CohenM. M. (2006). Holoprosencephaly: clinical, anatomic and molecular dimensions. Birth Defects Res. A Clin. Mol. Teratol.76, 658–673. 10.1002/bdra.20295

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  CohenM. M.ShiotaK. (2002). Teratogenesis of holoprosencephaly. Am. J. Med. Genet.109, 1–15. 10.1002/ajmg.10258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  ConteI.MorcilloJ.BovolentaP. (2005). Comparative analysis of Six 3 and Six 6 distribution in the developing and adult mouse brain. Dev. Dyn.234, 718–725. 10.1002/dvdy.20463

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  CorderoD.MarcucioR.HuD.GaffieldW.TapadiaM.HelmsJ. A. (2004). Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J. Clin. Invest.114, 485–494. 10.1172/JCI19596

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  CormanT. S.BergendahlS. E.EpsteinD. J. (2018). Distinct temporal requirements for Sonic hedgehog signaling in development of the tuberal hypothalamus. Development145:dev167379. 10.1242/dev.167379

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  CroizierS.ChomettonS.FellmannD.RisoldP. Y. (2014). Characterization of a mammalian prosencephalic functional plan. Front. Neuroanat.8:161.10.3389/fnana.2014.00161

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  CrossleyP. H.MartinG. R. (1995). The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development121, 439–451.

  • Pubmed Abstract
  • Google Scholar

• 49

  CrossleyP. H.MartinezS.MartinG. R. (1996). Midbrain development induced by FGF8 in the chick embryo. Nature380, 66–68. 10.1038/380066a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  CrossleyP. H.MartinezS.OhkuboY.RubensteinJ. L. (2001). Coordinate expression of Fgf8, Otx2, Bmp4 and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Neuroscience108, 183–206. 10.1016/s0306-4522(01)00411-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  DaleK.SattarN.HeemskerkJ.ClarkeJ. D.PlaczekM.DoddJ. (1999). Differential patterning of ventral midline cells by axial mesoderm is regulated by BMP7 and chordin. Development126, 397–408.

  • Pubmed Abstract
  • Google Scholar

• 52

  DaleJ. K.VesqueC.LintsT. J.SampathT. K.FurleyA.DoddJ.et al. (1997). Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell90, 257–269. 10.1016/s0092-8674(00)80334-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  DasenJ. S.RosenfeldM. G. (2001). Signaling and transcriptional mechanisms in pituitary development. Annu. Rev. Neurosci.24, 327–355. 10.1146/annurev.neuro.24.1.327

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  DattaniM. T.Martinez-BarberaJ. P.ThomasP. Q.BrickmanJ. M.GuptaR.MårtenssonI. L.et al. (1998). Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat. Genet.19, 125–133. 10.1038/477

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  DavidsonE. H. (2006). The Regulatory Genome: Gene Regulatory Networks in Development and Evolution.San Diego, CA: Academic Press, Elsevier.

  • Google Scholar

• 56

  DavisS. W.CamperS. A. (2007). Noggin regulates Bmp4 activity during pituitary induction. Dev. Biol.305, 145–160. 10.1016/j.ydbio.2007.02.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  De RobertisE. M.SasaiY. (1996). A common plan for dorsoventral patterning in Bilateria. Nature380, 37–40. 10.1038/380037a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  Del GiaccoL.SordinoP.PistocchiA.AndreakisN.TaralloR.Di BenedettoB.et al. (2006). Differential regulation of the zebrafish orthopedia 1 gene during fate determination of diencephalic neurons. BMC Dev. Biol.6:50.10.1186/1471-213X-6-50

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  DíazC.Morales-DelgadoN.PuellesL. (2015). Ontogenesis of peptidergic neurons within the genoarchitectonic map of the mouse hypothalamus. Front. Neuroanat.8:162. 10.3389/fnana.2014.00162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  Diez-RouxG.BanfiS.SultanM.GeffersL.AnandS.RozadoD.et al. (2011). A high-resolution anatomical atlas of the transcriptome in the mouse embryo. PLoS Biol.9:e1000582. 10.1371/journal.pbio.1000582

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  DinizG. B.BattagelloD. S.CherubiniP. M.Reyes-MendozaJ. D.Luna-IlladesC.KleinM. O.et al. (2019). Melanin-concentrating hormone peptidergic system: comparative morphology between muroid species. J. Comp. Neurol.527, 2973–3001. 10.1002/cne.24723

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  DomenéS.RoesslerE.El-JaickK. B.SnirM.BrownJ. L.VélezJ. I.et al. (2008). Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum. Mol. Genet.17, 3919–3928. 10.1093/hmg/ddn294

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  DomínguezL.GonzálezA.MorenoN. (2011). Ontogenetic distribution of the transcription factor nkx2.2 in the developing forebrain of Xenopus laevis. Front. Neuroanat.5:11. 10.3389/fnana.2011.00011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  DomínguezL.GonzálezA.MorenoN. (2014). Characterization of the hypothalamus of Xenopus laevis during development. II. The basal regions. J. Comp. Neurol.522, 1102–1131. 10.1002/cne.23471

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  DomínguezL.GonzálezA.MorenoN. (2015). Patterns of hypothalamic regionalization in amphibians and reptiles: common traits revealed by a genoarchitectonic approach. Front. Neuroanat.9:3.10.3389/fnana.2015.00003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  DomínguezL.MoronaR.GonzálezA.MorenoN. (2013). Characterization of the hypothalamus of Xenopus laevis during development. I. The alar regions. J. Comp. Neurol.521, 725–759. 10.1002/cne.23222

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  DoniachT. (1993). Planar and vertical induction of anteroposterior pattern during the development of the amphibian central nervous system. J. Neurobiol.24, 1256–1275. 10.1002/neu.480241003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  DownsK. M.DaviesT. (1993). Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope. Development118, 1255–1266.

  • Pubmed Abstract
  • Google Scholar

• 69

  DubourgC.BendavidC.PasquierL.HenryC.OdentS.DavidV. (2007). Holoprosencephaly. Orphanet J. Rare Dis.2:8.10.1186/1750-1172-2-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  DubourgC.CarréW.Hamdi-RozéH.MoudenC.RoumeJ.AbdelmajidB.et al. (2016). Mutational spectrum in holoprosencephaly shows that FGF is a new major signaling pathway. Hum. Mutat.37, 1329–1339. 10.1002/humu.23038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  DubourgC.KimA.WatrinE.de TayracM.OdentS.DavidV.et al. (2018). Recent advances in understanding inheritance of holoprosencephaly. Am. J. Med. Genet. C Semin. Med. Genet.178, 258–269. 10.1002/ajmg.c.31619

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  DubourgC.LazaroL.PasquierL.BendavidC.BlayauM.Le DuffF.et al. (2004). Molecular screening of SHH, ZIC2, SIX3 and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations. Hum. Mutat.24, 43–51. 10.1002/humu.20056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  Dutra de Oliveira MeloE. (2011). Estudio del Patrón de Expresión del gen Homeobox Six3 en el Cerebro Embrionario de Pollo y Ratón: Análisis en Relación al Modelo Prosomérico.Universidad de Murcia. Available online at: https://digitum.um.es/digitum/handle/10201/34549.

  • Google Scholar

• 74

  EaglesonG.FerreiroB.HarrisW. A. (1995). Fate of the anterior neural ridge and the morphogenesis of the Xenopus forebrain. J. Neurobiol.28, 146–158. 10.1002/neu.480280203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  EchelardY.EpsteinD. J.St-JacquesB.ShenL.MohlerJ.McMahonJ. A.et al. (1993). Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell75, 1417–1430. 10.1016/0092-8674(93)90627-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  EchevarríaD.VieiraC.GimenoL.MartínezS. (2003). Neuroepithelial secondary organizers and cell fate specification in the developing brain. Brain Res. Rev.43, 179–191. 10.1016/j.brainresrev.2003.08.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  EricsonJ.MuhrJ.JessellT. M.EdlundT. (1995a). Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal axis of the neural tube. Int. J. Dev. Biol.39, 809–816.

  • Pubmed Abstract
  • Google Scholar

• 78

  EricsonJ.MuhrJ.PlaczekM.LintsT.JessellT. M.EdlundT. (1995b). Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube. Cell81, 747–756. 10.1016/0092-8674(95)90536-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  EricsonJ.NorlinS.JessellT. M.EdlundT. (1998). Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development125, 1005–1015.

  • Pubmed Abstract
  • Google Scholar

• 80

  FanC. M.KuwanaE.BulfoneA.FletcherC. F.CopelandN. G.JenkinsN. A.et al. (1996). Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. Mol. Cel. Neurosci.7, 1–16. 10.1006/mcne.1996.0001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  FerranJ. L.PuellesL.RubensteinJ. L. (2015). Molecular codes defining rostrocaudal domains in the embryonic mouse hypothalamus. Front. Neuroanat.9:46. 10.3389/fnana.2015.00046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  FlamesN.PlaR.GelmanD. M.RubensteinJ. L.PuellesL.MarínO. (2007). Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci.27, 9682–9695. 10.1523/JNEUROSCI.2750-07.2007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  FuT.PearsonC.TowersM.PlaczekM. (2019). Development of the basal hypothalamus through anisotropic growth. J. Neuroendocrinol.31:e12727. 10.1111/jne.12727

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  FuT.TowersM.PlaczekM. A. (2017). Fgf10+ progenitors give rise to the chick hypothalamus by rostral and caudal growth and differentiation. Development144, 3278–3288. 10.1242/dev.153379

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  FujinagaM.BrownN. A.BadenJ. M. (1992). Comparison of staging systems for the gastrulation and early neurulation period in rodents: a proposed new system. Teratology46, 183–190. 10.1002/tera.1420460211

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  Fukuchi-ShimogoriT.GroveE. A. (2001). Neocortex patterning by the secreted signaling molecule FGF8. Science294, 1071–1074. 10.1126/science.1064252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  García-CaleroE.Fernández-GarreP.MartínezS.PuellesL. (2008). Early mammillary pouch specification in the course of prechordal ventralization of the forebrain tegmentum. Dev. Biol.320, 366–377. 10.1016/j.ydbio.2008.05.545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  García-LópezM.AbellánA.LegazI.RubensteinJ. L.PuellesL.MedinaL. (2008). Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development. J. Comp. Neurol.506, 46–74. 10.1002/cne.21524

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  GardaA. L.PuellesL.RubensteinJ. L.MedinaL. (2002). Expression patterns of Wnt8b and Wnt7b in the chicken embryonic brain suggest a correlation with forebrain patterning centers and morphogenesis. Neuroscience113, 689–698. 10.1016/s0306-4522(02)00171-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  GarelS.HuffmanK. J.RubensteinJ. L. (2003). Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development130, 1903–1914. 10.1242/dev.00416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  GarneE.RissmannA.AddorM. C.BarisicI.BergmanJ.BrazP.et al. (2018). Epidemiology of septo-optic dysplasia with focus on prevalence and maternal age—A EUROCAT study. Eur. J. Med. Genet.61, 483–488. 10.1016/j.ejmg.2018.05.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  GeeraedtsL. M.NieuwenhuysR.VeeningJ. G. (1990a). Medial forebrain bundle of the rat: III. Cytoarchitecture of the rostral (telencephalic) part of the medial forebrain bundle bed nucleus. J. Comp. Neurol.294, 507–536. 10.1002/cne.902940403

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  GeeraedtsL. M.NieuwenhuysR.VeeningJ. G. (1990b). Medial forebrain bundle of the rat: IV. Cytoarchitecture of the caudal (lateral hypothalamic) part of the medial forebrain bundle bed nucleus. J. Comp. Neurol.294, 537–568. 10.1002/cne.902940404

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  GelmanD.GriveauA.DehorterN.TeissierA.VarelaC.PlaR.et al. (2011). A wide diversity of cortical GABAergic interneurons derives from the embryonic preoptic area. J. Neurosci.31, 16570–16580. 10.1523/JNEUROSCI.4068-11.2011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  GelmanD. M.MartiniF. J.Nóbrega-PereiraS.PieraniA.KessarisN.MarínO. (2009). The embryonic preoptic area is a novel source of cortical GABAergic interneurons. J. Neurosci.29, 9380–9389. 10.1523/JNEUROSCI.0604-09.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  GengX.AcostaS.LagutinO.GilH. J.OliverG. (2016). Six3 dosage mediates the pathogenesis of holoprosencephaly. Development143, 4462–4473. 10.1242/dev.132142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  GengX.SpeirsC.LagutinO.InbalA.LiuW.Solnica-KrezelL.et al. (2008). Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev. Cell15, 236–247. 10.1016/j.devcel.2008.07.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  GilbertM. (1935). The early development of the human diencephalon. J. Comp. Neurol.62, 81–116.

  • Google Scholar

• 99

  GilletteM. U.TischkauS. A. (1999). Suprachiasmatic nucleus: the brain’s circadian clock. Recent Prog. Horm. Res.54, 33–58; discussion 58–59.

  • Pubmed Abstract
  • Google Scholar

• 100

  GimenoL.HashemiR.BrûletP.MartínezS. (2002). Analysis of Fgf15 expression pattern in the mouse neural tube. Brain Res. Bull.57, 297–299. 10.1016/s0361-9230(01)00717-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  GonzalezA.LopezJ.MoronaR.MorenoN. (2017). “The organization of the central nervous system of amphibians,” in The Evolution of the Nervous Systems in Nonmammalian Vertebrates, ed. StriedterG. (Amsterdam: Academic Press/Elsevier), 141–170.

  • Google Scholar

• 102

  GribnauA. A.GeijsbertsL. G. (1985). Morphogenesis of the brain in staged rhesus monkey embryos. Adv. Anat. Embryol. Cell Biol.91, 1–69. 10.1007/978-3-642-69953-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  GurdonJ. B.BourillotP. Y. (2001). Morphogen gradient interpretation. Nature413, 797–803. 10.1038/35101500

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  Haddad-TóvolliR.PaulF. A.ZhangY.ZhouX.TheilT.PuellesL.et al. (2015). Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Front. Neuroanat.9:34. 10.3389/fnana.2015.00034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  Hamdi-RozéH.WareM.GuyodoH.RizzoA.RatiéL.RupinM.et al. (2020). Disrupted hypothalamo-pituitary axis in association with reduced SHH underlies the pathogenesis of NOTCH-deficiency. J. Clin. Endocrinol. Metab.105:dgaa249. 10.1210/clinem/dgaa249

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  HauptmannG.SöllI.GersterT. (2002). The early embryonic zebrafish forebrain is subdivided into molecularly distinct transverse and longitudinal domains. Brain Res. Bull.57, 371–375. 10.1016/s0361-9230(01)00691-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  HeideM.ZhangY.ZhouX.ZhaoT.MiquelajáureguiA.Varela-EchavarríaA.et al. (2015). Lhx5 controls mamillary differentiation in the developing hypothalamus of the mouse. Front. Neuroanat.9:113. 10.3389/fnana.2015.00113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  HeisenbergC. P.BrennanC.WilsonS. W. (1999). Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development. Development126, 2129–2140.

  • Pubmed Abstract
  • Google Scholar

• 109

  HermeszE.MackemS.MahonK. A. (1996). Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke’s pouch of the mouse embryo. Development122, 41–52.

  • Pubmed Abstract
  • Google Scholar

• 110

  HerrickC. (1910). The morphology of the forebrain in amphibia and reptilia. J. Comp. Neurol.20, 413–547.

  • Google Scholar

• 111

  HerzogE. D.HermanstyneT.SmyllieN. J.HastingsM. H. (2017). Regulating the suprachiasmatic nucleus (SCN) circadian clockwork: interplay between cell-autonomous and circuit-level mechanisms. Cold Spring Harb. Perspect. Biol.9:a027706. 10.1101/cshperspect.a027706

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  HirataT.LiP.LanuzaG. M.CocasL. A.HuntsmanM. M.CorbinJ. G. (2009). Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala. Nat. Neurosci.12, 141–149. 10.1038/nn.2241

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  HisW. (1893). Vorschläge zur Eintheilung des Gehirns. Arch. Anat. Entwickelungsges3, 172–179.

  • Google Scholar

• 114

  HisW. (1904). Die Entwicklung des Menschlichen Gehirns Während der Ersten Monate.Leipzig: Hirzel.

  • Google Scholar

• 115

  HochstetterF. (1919). Beiträge zur Entwicklungsgeschichte des Menschlichen Gehirns. Part I.Leipzig: Deuticke.

  • Google Scholar

• 116

  HochstetterF. (1923). Beiträge zur Entwicklungsgeschichte des Menschlichen Gehirns. Teil II. 1. Lieferung. Die Entwicklung der Zirbeldrüse.Vienna: Deuticke.

  • Google Scholar

• 117

  HochstetterF. (1929). Beiträge zur Entwicklungsgeschichte des Menschlichen Gehirns. Teil II. 2. Lieferung. Die Entwicklung des Mittel- und Rautenhirns.Vienna: Deuticke.

  • Google Scholar

• 118

  HolleyS. A.JacksonP. D.SasaiY.LuB.De RobertisE. M.HoffmannF. M.et al. (1995). A conserved system for dorsal-ventral patterning in insects and vertebrates involving sog and chordin. Nature376, 249–253. 10.1038/376249a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  HongM.KraussR. S. (2012). Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS Genet.8:e1002999. 10.1371/journal.pgen.1002999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  HongM.KraussR. S. (2017). Ethanol itself is a holoprosencephaly-inducing teratogen. PLoS One12:e0176440. 10.1371/journal.pone.0176440

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  HouartC.CaneparoL.HeisenbergC.BarthK.Take-UchiM.WilsonS. (2002). Establishment of the telencephalon during gastrulation by local antagonism of Wnt signaling. Neuron35, 255–265. 10.1016/s0896-6273(02)00751-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  HouartC.WesterfieldM.WilsonS. W. (1998). A small population of anterior cells patterns the forebrain during zebrafish gastrulation. Nature391, 788–792. 10.1038/35853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  HynesM.PorterJ. A.ChiangC.ChangD.Tessier-LavigneM.BeachyP. A.et al. (1995). Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron15, 35–44. 10.1016/0896-6273(95)90062-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  JeongY.EpsteinD. J. (2003). Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Development130, 3891–3902. 10.1242/dev.00590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  JeongY.LeskowF. C.El-JaickK.RoesslerE.MuenkeM.YocumA.et al. (2008). Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat. Genet.40, 1348–1353. 10.1038/ng.230

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  KapsimaliM.CaneparoL.HouartC.WilsonS. W. (2004). Inhibition of Wnt/Axin/β-catenin pathway activity promotes ventral CNS midline tissue to adopt hypothalamic rather than floorplate identity. Development131, 5923–5933. 10.1242/dev.01453

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  KauvarE. F.MuenkeM. (2010). Holoprosencephaly: recommendations for diagnosis and management. Curr. Opin. Pediatr.22, 687–695. 10.1097/MOP.0b013e32833f56d5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  KelbermanD.DattaniM. T. (2006). The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism. Ann. Med.38, 560–577. 10.1080/07853890600994963

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  KelbermanD.DattaniM. T. (2007a). Hypopituitarism oddities: congenital causes. Horm. Res.68, 138–144. 10.1159/000110610

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  KelbermanD.DattaniM. T. (2007b). Hypothalamic and pituitary development: novel insights into the aetiology. Eur. J. Endocrinol.157, S3–S14. 10.1530/EJE-07-0156

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  KelbermanD.DattaniM. T. (2008). Septo-optic dysplasia—novel insights into the aetiology. Horm. Res.69, 257–265. 10.1159/000114856

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  KelbermanD.RizzotiK.Lovell-BadgeR.RobinsonI. C.DattaniM. T. (2009). Genetic regulation of pituitary gland development in human and mouse. Endocr. Rev.30, 790–829. 10.1210/er.2009-0008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  KietzmanH. W.EversonJ. L.SulikK. K.LipinskiR. J. (2014). The teratogenic effects of prenatal ethanol exposure are exacerbated by Sonic Hedgehog or GLI2 haploinsufficiency in the mouse. PLoS One9:e89448. 10.1371/journal.pone.0089448

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  KimJ. W.LemkeG. (2006). Hedgehog-regulated localization of Vax2 controls eye development. Genes Dev.20, 2833–2847. 10.1101/gad.1462706

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  KimA.SavaryC.DubourgC.CarréW.MoudenC.Hamdi-RozéH.et al. (2019). Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly. Brain142, 35–49. 10.1093/brain/awy290

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  KinderS. J.TsangT. E.WakamiyaM.SasakiH.BehringerR. R.NagyA.et al. (2001). The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development128, 3623–3634.

  • Pubmed Abstract
  • Google Scholar

• 137

  KingsburyB. F. (1930). The developmental significance of the floor plate of the brain and spinal cord. J. Comp. Neurol.50, 177–207. 10.1002/cne.900500109

  • CrossRef
  • Google Scholar

• 138

  KoutcherovY.MaiJ. K.PaxinosG. (2003). Hypothalamus of the human fetus. J. Chem. Neuroanat.26, 253–270. 10.1016/j.jchemneu.2003.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  KuhlenbeckH. (1927). Vorlesungen Über das Zentrarlnervensystem der Wirbeltiere. Jena: Fisher.

  • Google Scholar

• 140

  KuhlenbeckH. (1954). The Human Diencephalon. Basel: Karger.

  • Google Scholar

• 141

  KuhlenbeckH. (1973). The Central Nervous System of Vertebrates. Vol.3. Part II: Overall Morphologic Pattern.Basel: S. Karger.

  • Google Scholar

• 142

  KuhlenbeckH.HaymakerW. (1949). The derivatives of the hypothalamus in the human brain: their relation to the extrapyramidal and autonomous systems. Mil. Surg.105, 26–52.

  • Pubmed Abstract
  • Google Scholar

• 143

  LagutinO. V.ZhuC. C.KobayashiD.TopczewskiJ.ShimamuraK.PuellesL.et al. (2003). Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev.17, 368–379. 10.1101/gad.1059403

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  LeeB.RizzotiK.KwonD. S.KimS. Y.OhS.EpsteinD. J.et al. (2012). Direct transcriptional regulation of Six6 is controlled by SoxB1 binding to a remote forebrain enhancer. Dev. Biol.366, 393–403. 10.1016/j.ydbio.2012.04.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  LeonciniE.BaranelloG.OrioliI. M.AnnerénG.BakkerM.BianchiF.et al. (2008). Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res. A Clin. Mol. Teratol.82, 585–591. 10.1002/bdra.20479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  LiH.TierneyC.WenL.WuJ. Y.RaoY. (1997). A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate. Development124, 603–615.

  • Pubmed Abstract
  • Google Scholar

• 147

  LiS.YipA.BirdJ.SeokB. S.ChanA.GoddenK. E.et al. (2018). Melanin-concentrating hormone (MCH) neurons in the developing chick brain. Brain Res.1700, 19–30. 10.1016/j.brainres.2018.07.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  LipinskiR. J.BushmanW. (2010). Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol. in vitro24, 1404–1409. 10.1016/j.tiv.2010.04.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  LipinskiR. J.GodinE. A.O’Leary-MooreS. K.ParnellS. E.SulikK. K. (2010). Genesis of teratogen-induced holoprosencephaly in mice. Am. J. Med. Genet. C Semin. Med. Genet.154C, 29–42. 10.1002/ajmg.c.30239

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  López-RíosJ.TessmarK.LoosliF.WittbrodtJ.BovolentaP. (2003). Six3 and Six6 activity is modulated by members of the groucho family. Development130, 185–195. 10.1242/dev.00185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  ManningL.OhyamaK.SaegerB.HatanoO.WilsonS. A.LoganM.et al. (2006). Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation. Dev. Cell11, 873–885. 10.1016/j.devcel.2006.09.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  MarinO.AndersonS. A.RubensteinJ. L. (2000). Origin and molecular specification of striatal interneurons. J. Neurosci.20, 6063–6076. 10.1523/JNEUROSCI.20-16-06063.2000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  MartíE.BumcrotD. A.TakadaR.McMahonA. P. (1995). Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature375, 322–325. 10.1038/375322a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  MartínezS. (2001). The isthmic organizer and brain regionalization. Int. J. Dev. Biol.45, 367–371.

  • Pubmed Abstract
  • Google Scholar

• 155

  MartinezS.CrossleyP. H.CobosI.RubensteinJ. L.MartinG. R. (1999). FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development126, 1189–1200.

  • Pubmed Abstract
  • Google Scholar

• 156

  MaruokaY.OhbayashiN.HoshikawaM.ItohN.HoganB. L.FurutaY. (1998). Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo. Mech. Dev.74, 175–177. 10.1016/s0925-4773(98)00061-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  McCabeM. J.Gaston-MassuetC.TziaferiV.GregoryL. C.AlatzoglouK. S.SignoreM.et al. (2011). Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects and hypothalamo-pituitary dysfunction. J. Clin.Endocr. Metab.96, E1709–E1718. 10.1210/jc.2011-0454

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  McNayD. E.TurtonJ. P.KelbermanD.WoodsK. S.BraunerR.PapadimitriouA.et al. (2007). HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J. Clin. Endocrinol. Metab.92, 691–697. 10.1210/jc.2006-1609

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  MedinaL.AbellánA. (2012). “Subpallial structures,” in The Mouse Nervous System, WatsonC.PaxinosG.PuellesL. (London: Elsevier Academic Press), 173–220.

  • Google Scholar

• 160

  MercierS.DavidV.RatiéL.GicquelI.OdentS.DupéV. (2013). NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. Dis. Model Mech.6, 537–543. 10.1242/dmm.010132

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  MercierS.DubourgC.GarcelonN.Campillo-GimenezB.GicquelI.BelleguicM.et al. (2011). New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J. Med. Genet.48, 752–760. 10.1136/jmedgenet-2011-100339

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  MeyersE. N.LewandoskiM.MartinG. R. (1998). An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat. Genet.18, 136–141. 10.1038/ng0298-136

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  MichaudJ. L.RosenquistT.MayN. R.FanC. M. (1998). Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Gen. Dev.12, 3264–3275. 10.1101/gad.12.20.3264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  MillerE. A.RasmussenS. A.Siega-RizA. M.FríasJ. L.HoneinM. A.National Birth Defects Prevention Study. (2010). Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am. J. Med. Genet. C Semin. Med. Genet.154C, 62–72. 10.1002/ajmg.c.30244

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  Morales-DelgadoN.Castro-RoblesB.FerránJ. L.Martinez-de-la-TorreM.PuellesL.DíazC. (2014). Regionalized differentiation of CRH, TRH, and GHRH peptidergic neurons in the mouse hypothalamus. Brain Struct. Funct.219, 1083–1111. 10.1007/s00429-013-0554-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  Morales-DelgadoN.MerchanP.BardetS.FerranJ. L.DíazC. (2011). Topography of somatostatin gene expression relative to molecular progenitor domains during ontogeny of the mouse hypothalamus. Front. Neuroanat.5:10. 10.3389/fnana.2011.00010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  MorenoN.DomínguezL.MoronaR.GonzálezA. (2012). Subdivisions of the turtle Pseudemys scripta hypothalamus based on the expression of regulatory genes and neuronal markers. J. Comp. Neurol.520, 453–478. 10.1002/cne.22762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  MotoyamaJ.MilenkovicL.IwamaM.ShikataY.ScottM. P.HuiC. C. (2003). Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev. Biol.259, 150–161. 10.1016/s0012-1606(03)00159-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  MüllerF.O’RahillyR. (1988). The development of the human brain, including the longitudinal zoning in the diencephalon at stage 15. Anat. Embryol.179, 55–71. 10.1007/BF00305100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  MüllerF.O’RahillyR. (1989a). The human brain at stage 16, including the initial evagination of the neurohypophysis. Anat. Embryol.179, 551–569. 10.1007/BF00315698

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  MüllerF.O’RahillyR. (1989b). The human brain at stage 17, including the appearance of the future olfactory bulb and the first amygdaloid nuclei. Anat. Embryol.180, 353–369. 10.1007/BF00311167

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  MüllerF.O’RahillyR. (1990a). The human brain at stages 18–20, including the choroid plexuses and the amygdaloid and septal nulcei. Anat. Embryol.182, 285–306. 10.1007/BF00185521

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  MüllerF.O’RahillyR. (1990b). The human brain at stages 21–23, with particular reference to the cerebral cortical plate and to the development of the cerebellum. Anat. Embryol.182, 375–400. 10.1007/BF02433497

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  MüllerF.O’RahillyR. (2003). The prechordal plate, the rostral end of the notochord and nearby median features in staged human embryos. Cells Tissues Organs. 173, 1–20. 10.1159/000068214

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  NanniL.MingJ. E.BocianM.SteinhausK.BianchiD. W.Die-SmuldersC.et al. (1999). The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum. Mol. Genet.8, 2479–2488. 10.1093/hmg/8.13.2479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  NeryS.WichterleH.FishellG. (2001). Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development128, 527–540.

  • Pubmed Abstract
  • Google Scholar

• 177

  Nguengang WakapS.LambertD. M.OlryA.RodwellC.GueydanC.LanneauV.et al. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet.28, 165–173. 10.1038/s41431-019-0508-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  NieuwenhuysR.PuellesL. (2016). Towards a New Neuromorphology.New York, NY: Springer.

  • Google Scholar

• 179

  NieuwenhuysR.GeeraedtsL. M.VeeningJ. G. (1982). The medial forebrain bundle of the rat. I. General introduction. J. Comp. Neurol.206, 49–81. 10.1002/cne.902060106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  O’RahillyF.MüllerR. (1999). The Embryonic Human Brain. An Atlas of Developmental Stages.New York, NY: John Wiley and Sons Inc.

  • Google Scholar

• 181

  OhkuboY.ChiangC.RubensteinJ. L. (2002). Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. Neuroscience111, 1–17. 10.1016/s0306-4522(01)00616-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  OhuchiH.HoriY.YamasakiM.HaradaH.SekineK.KatoS.et al. (2000). FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem. Biophys. Res. Commun.277, 643–649. 10.1006/bbrc.2000.3721

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  OkadaT.OkumuraY.MotoyamaJ.OgawaM. (2008). FGF8 signaling patterns the telencephalic midline by regulating putative key factors of midline development. Dev. Biol.320, 92–101. 10.1016/j.ydbio.2008.04.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  OlivierC.CobosI.Perez VillegasE. M.SpasskyN.ZalcB.MartinezS.et al. (2001). Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo. Development128, 1757–1769.

  • Pubmed Abstract
  • Google Scholar

• 185

  OliverG.MailhosA.WehrR.CopelandN. G.JenkinsN. A.GrussP. (1995). Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development121, 4045–4055.

  • Pubmed Abstract
  • Google Scholar

• 186

  OrioliI. M.CastillaE. E. (2010). Epidemiology of holoprosencephaly: prevalence and risk factors. Am. J. Med. Genet. C Semin. Med. Genet.154C, 13–21. 10.1002/ajmg.c.30233

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  OsmundsenA. M.KeislerJ. L.TaketoM. M.DavisS. W. (2017). Canonical WNT signaling regulates the pituitary organizer and pituitary gland formation. Endocrinology158, 3339–3353. 10.1210/en.2017-00581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  PaekH.GutinG.HébertJ. M. (2009). FGF signaling is strictly required to maintain early telencephalic precursor cell survival. Development136, 2457–2465. 10.1242/dev.032656

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  PapezJ. W. (1940). The embryonic development of the hypothalamic area in mammals. Proc. Assoc. Res. Nerv. Ment. Dis.20, 31–51.

  • Google Scholar

• 190

  ParkinsonN.CollinsM. M.DufresneL.RyanA. K. (2010). Expression patterns of hormones, signaling molecules, and transcription factors during adenohypophysis development in the chick embryo. Dev. Dyn.239, 1197–1210. 10.1002/dvdy.22250

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  PengG.WesterfieldM. (2006). Lhx5 promotes forebrain development and activates transcription of secreted Wnt antagonists. Development133, 3191–3200. 10.1242/dev.02485

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  PeraE. M.KesselM. (1997). Patterning of the chick forebrain anlage by the prechordal plate. Development124, 4153–4162.

  • Pubmed Abstract
  • Google Scholar

• 193

  PetrykA.GrafD.MarcucioR. (2015). Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley Interdiscip. Rev. Dev. Biol.4, 17–32. 10.1002/wdev.161

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  Pineda-AlvarezD. E.DubourgC.DavidV.RoesslerE.MuenkeM. (2010). Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients. Am. J. Med. Genet. C Semin. Med. Genet.154C, 93–101. 10.1002/ajmg.c.30253

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  PlaczekM.BriscoeJ. (2005). The floor plate: multiple cells, multiple signals. Nat. Rev. Neurosci.6, 230–240. 10.1038/nrn1628

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  PlaczekM.DoddJ.JessellT. M. (2000). Discussion point. The case for floor plate induction by the notochord. Curr. Opin. Neurobiol.10, 15–22. 10.1016/s0959-4388(99)00060-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  PlaczekM.FuT.TowersM. (2020). “Development of the Neuroendocrine Hypothalamus,” in Developmental Neuroendocrinology, eds WrayS.BlackshawS. (Switzerland: Springer Nature Switzerland), 3–30.

  • Google Scholar

• 198

  PlaczekM.JessellT. M.DoddJ. (1993). Induction of floor plate differentiation by contact-dependent, homeogenetic signals. Development117, 205–218.

  • Pubmed Abstract
  • Google Scholar

• 199

  PlaczekM.YamadaT.Tessier-LavigneM.JessellT.DoddJ. (1991). Control of dorsoventral pattern in vertebrate neural development: induction and polarizing properties of the floor plate. Dev. Suppl.2, 105–122.

  • Pubmed Abstract
  • Google Scholar

• 200

  PontecorviM.GodingC. R.RichardsonW. D.KessarisN. (2008). Expression of Tbx2 and Tbx3 in the developing hypothalamic-pituitary axis. Gene Expr. Patterns8, 411–417. 10.1016/j.gep.2008.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  PotokM. A.ChaK. B.HuntA.BrinkmeierM. L.LeitgesM.KispertA.et al. (2008). WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth. Dev. Dyn.237, 1006–1020. 10.1002/dvdy.21511

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  PuellesL. (1995). A segmental morphological paradigm for understanding vertebrate forebrains. Brain Behav. Evol.46, 319–337. 10.1159/000113282

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  PuellesL. (1996). Atlas of prenatal rat brain development (book review of Altman and Bayer, 1995). Trends Neurosci.19, 116–117. 10.1016/S0166-2236(96)80042-7

  • CrossRef
  • Google Scholar

• 204

  PuellesL. (2013). “Plan of the developing vertebrate nervous system relating embryology to the adult nervous system (prosomere model, overview of brain organization),” in Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS, eds RubensteinJ.L.R.RakicP. (Amsterdam: Academic Press), 187–209.

  • Google Scholar

• 205

  PuellesL. (2017). “Forebrain development in vertebrates. The evolutionary role of secondary organizers,” in The Wiley Handbook of Evolutionary Neuroscience, ed. ShepherdS. V. (West Sussex: John Wiley and Sons), 351–387.

  • Google Scholar

• 206

  PuellesL. (2019). Survey of midbrain, diencephalon, and hypothalamus neuroanatomic terms whose prosomeric definition conflicts with columnar tradition. Front. Neuroanat.13:20. 10.3389/fnana.2019.00020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  PuellesL.AmatJ. A.Martinez-de-la-TorreM. (1987). Segment-related, mosaic neurogenetic pattern in the forebrain and mesencephalon of early chick embryos: I. Topography of AChE-positive neuroblasts up to stage HH18. J. Comp. Neurol.266, 247–268. 10.1002/cne.902660210

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  PuellesL.DiazC.StühmerT.FerranJ. L.Martínez-de la TorreM.RubensteinJ. L. R. (2020). LacZ-reporter mapping of Dlx5/6 expression and genoarchitectural analysis of the postnatal mouse prethalamus. J. Comp. Neurol. [Epub ahead of print]. 10.1002/cne.24952

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  PuellesL.FerranJ. L. (2012). Concept of neural genoarchitecture and its genomic fundament. Front. Neuroanat.6:47. 10.3389/fnana.2012.00047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  PuellesL.HarrisonM.PaxinosG.WatsonC. (2013). A developmental ontology for the mammalian brain based on the prosomeric model. Trends Neurosci.36, 570–578. 10.1016/j.tins.2013.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  PuellesL.KuwanaE.PuellesE.BulfoneA.ShimamuraK.KeleherJ.et al. (2000). Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6 and Tbr-1. J. Comp. Neurol.424, 409–438. 10.1002/1096-9861(20000828)424:3<409::aid-cne3>3.0.co;2-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  PuellesL.MartinezS. (2013). “Patterning of the diencephalon,” in Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification Developing CNS and PNS, eds RubensteinJ. L. R.RakicP. (Amsterdam: Elsevier), 151–172.

  • Google Scholar

• 213

  PuellesL.MartinezS.Martinez-de-la-TorreM.RubensteinJ. L. R. (2004). “Gene maps and related histogenetic domains in the forebrain and midbrain,” in The Rat Nervous System, ed. PaxinosG. (San Diego: Academic Press), 3–25.

  • Google Scholar

• 214

  PuellesL.Martinez-de-la-TorreM.BardetS. M.RubensteinJ. L. R. (2012). “Hypothalamus,” in The Mouse Nervous System, eds WatsonC.PaxinosG.PuellesL. (London: Elsevier Academic Press), 221–312.

  • Google Scholar

• 215

  PuellesL.MilánF.Martínez-de-la-TorreM. (1996). A segmental map of architectonic subdivisions in the diencephalon of the frog Rana perezi: acetylcholinesterase-histochemical observations. Brain Behav. Evol.47, 279–310. 10.1159/000113247

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  PuellesL.Morales-DelgadoN.MerchánP.Castro-RoblesB.Martínez-de-la-TorreM.DíazC.et al. (2016). Radial and tangential migration of telencephalic somatostatin neurons originated from the mouse diagonal area. Brain Struct. Funct.221, 3027–3065. 10.1007/s00429-015-1086-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  PuellesL.RubensteinJ. L. R. (2003). Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci.26, 469–476. 10.1016/S0166-2236(03)00234-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  PuellesL.RubensteinJ. L. R. (2015). A new scenario of hypothalamic organization: rationale of new hypotheses introduced in the updated prosomeric model. Front. Neuroanat.9:27. 10.3389/fnana.2015.00027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  RadyushkinK.AnokhinK.MeyerB. I.JiangQ.Alvarez-BoladoG.GrussP. (2005). Genetic ablation of the mammillary bodies in the Foxb1 mutant mouse leads to selective deficit of spatial working memory. Eur. J. Neurosci.21, 219–229. 10.1111/j.1460-9568.2004.03844.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  RizzotiK. (2015). Genetic regulation of murine pituitary development. J. Mol. Endocrinol.54, R55–R73. 10.1530/JME-14-0237

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  RizzotiK.BrunelliS.CarmignacD.ThomasP. Q.RobinsonI. C.Lovell-BadgeR. (2004). SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat. Genet.36, 247–255. 10.1038/ng1309

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  RizzotiK.Lovell-BadgeR. (2007). SOX3 activity during pharyngeal segmentation is required for craniofacial morphogenesis. Development134, 3437–3448. 10.1242/dev.007906

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  RodriguezK. M.StevensonE. L.StewartC. E.LinscottM. L.ChungW. C. (2015). Fibroblast growth factor 8 regulates postnatal development of paraventricular nucleus neuroendocrine cells. Behav. Brain Funct.11:34. 10.1186/s12993-015-0081-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  RoelinkH.AugsburgerA.HeemskerkJ.KorzhV.NorlinS.Ruiz i AltabaA.et al. (1994). Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell76, 761–775. 10.1016/0092-8674(94)90514-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  RoesslerE.MuenkeM. (2010). The molecular genetics of holoprosencephaly. Am. J. Med. Genet. C Semin. Med. Genet.154C, 52–61. 10.1002/ajmg.c.30236

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  RoesslerE.BelloniE.GaudenzK.JayP.BertaP.SchererS. W.et al. (1996). Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat. Genet.14, 357–360. 10.1038/ng1196-357

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  RoesslerE.HuP.MarinoJ.HongS.HartR.BergerS.et al. (2018). Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling. Hum. Mutat.39, 1416–1427. 10.1002/humu.23590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  RubensteinJ. L.ShimamuraK.MartinezS.PuellesL. (1998). Regionalization of the prosencephalic neural plate. Annu. Rev. Neurosci.21, 445–477. 10.1146/annurev.neuro.21.1.445

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  Ruiz i AltabaA. (1994). Pattern formation in the vertebrate neural plate. Trends Neurosci.17, 233–243. 10.1016/0166-2236(94)90006-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  Ruiz i AltabaA. (1998). Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development125, 2203–2212.

  • Pubmed Abstract
  • Google Scholar

• 231

  Ruiz i AltabaA.PreziosoV. R.DarnellJ. E.JessellT. M. (1993). Sequential expression of HNF-3 β and HNF-3 α by embryonic organizing centers: the dorsal lip/node, notochord and floor plate. Mech. Dev.44, 91–108. 10.1016/0925-4773(93)90060-b

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  SagaiT.AmanoT.MaenoA.AjimaR.ShiroishiT. (2019). SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization. Proc. Natl. Acad. Sci. U S A116, 23636–23642. 10.1073/pnas.1901732116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  SajediE.Gaston-MassuetC.SignoreM.AndoniadouC. L.KelbermanD.CastroS.et al. (2008). Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Dis. Model Mech.1, 241–254. 10.1242/dmm.000711

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  Sánchez-ArronesL.FerránJ. L.Hidalgo-SanchezM.PuellesL. (2015). Origin and early development of the chicken adenohypophysis. Front. Neuroanat.9:7. 10.3389/fnana.2015.00007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  Sánchez-ArronesL.FerránJ. L.Rodríguez-GallardoL.PuellesL. (2009). Incipient forebrain boundaries traced by differential gene expression and fate mapping in the chick neural plate. Dev. Biol.335, 43–65. 10.1016/j.ydbio.2009.08.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  Sánchez-ArronesL.SternC. D.BovolentaP.PuellesL. (2012). Sharpening of the anterior neural border in the chick by rostral endoderm signalling. Development139, 1034–1044. 10.1242/dev.067934

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  Santos-DuránG. N.Ferreiro-GalveS.MenuetA.MazanS.Rodríguez-MoldesI.CandalE. (2018). The shark basal hypothalamus: molecular prosomeric subdivisions and evolutionary trends. Front. Neuroanat.12:17. 10.3389/fnana.2018.00017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  Santos-DuránG. N.Ferreiro-GalveS.MenuetA.Quintana-UrzainquiI.MazanS.Rodríguez-MoldesI.et al. (2016). The shark alar hypothalamus: molecular characterization of prosomeric subdivisions and evolutionary trends. Front. Neuroanat.10:113. 10.3389/fnana.2016.00113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  Santos-DuránG. N.MenuetA.LagadecR.MayeurH.Ferreiro-GalveS.MazanS.et al. (2015). Prosomeric organization of the hypothalamus in an elasmobranch, the catshark Scyliorhinus canicula. Front. Neuroanat.9:37. 10.3389/fnana.2015.00037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  SasakiH.HoganB. L. (1994). HNF-3 β as a regulator of floor plate development. Cell76, 103–115. 10.1016/0092-8674(94)90176-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  SaperC. B.LowellB. B. (2014). The hypothalamus. Curr. Biol.24, R1111–R1116. 10.1016/j.cub.2014.10.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  SatoN.KamachiY.KondohH.ShimaY.MorohashiK.HorikawaR.et al. (2007). Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Eur. J. Endocrinol.156, 167–171. 10.1530/EJE-06-0606

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  SchellU.WienbergJ.KöhlerA.Bray-WardP.WardD. E.WilsonW. G.et al. (1996). Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. Hum. Mol. Genet.5, 223–229. 10.1093/hmg/5.2.223

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  SchredelsekerT.DrieverW. (2020). Conserved genoarchitecture of the basal hypothalamus in zebrafish embryos. Front. Neuroanat.14:3. 10.3389/fnana.2020.00003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  SchröderH. J.MoserN.HuggenbergerS. (2020). Neuroanatomy of the Mouse Brain. An Introduction.Berlin: Springer.

  • Google Scholar

• 246

  ShimamuraK.HartiganD. J.MartinezS.PuellesL.RubensteinJ. L. (1995). Longitudinal organization of the anterior neural plate and neural tube. Development121, 3923–3933.

  • Pubmed Abstract
  • Google Scholar

• 247

  ShimamuraK.HiranoS.McMahonA. P.TakeichiM. (1994). Wnt-1-dependent regulation of local E-cadherin and α N-catenin expression in the embryonic mouse brain. Development120, 2225–2234.

  • Pubmed Abstract
  • Google Scholar

• 248

  ShimamuraK.RubensteinJ. L. (1997). Inductive interactions direct early regionalization of the mouse forebrain. Development124, 2709–2718.

  • Pubmed Abstract
  • Google Scholar

• 249

  ShimogoriT.LeeD. A.Miranda-AnguloA.YangY.WangH.JiangL.et al. (2010). A genomic atlas of mouse hypothalamic development. Nat. Neurosci.13, 767–775. 10.1038/nn.2545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  SolomonB. D.LacbawanF.JainM.DomenéS.RoesslerE.MooreC.et al. (2009). A novel SIX3 mutation segregates with holoprosencephaly in a large family. Am. J. Med. Genet. A149A, 919–925. 10.1002/ajmg.a.32813

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  SpatzH. (1925). Über die Entwicklungsgeschichte der basalen Ganglien des menschliches G rosshirn. Erg. Bd Anat. Anz.60, 54–58.

  • Google Scholar

• 252

  SternC. D. (2001). Initial patterning of the central nervous system: how many organizers?Nat. Rev. Neurosci.2, 92–98. 10.1038/35053563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  StormE. E.GarelS.BorelloU.HebertJ. M.MartinezS.McConnellS. K.et al. (2006). Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development133, 1831–1844. 10.1242/dev.02324

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  StormE. E.RubensteinJ. L.MartinG. R. (2003). Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain. Proc. Natl. Acad. Sci. U S A100, 1757–1762. 10.1016/j.bbrc.2019.03.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  StriedterG. F. (2016). Neurobiology: A Functional Approach.London: Oxford University Press.

  • Google Scholar

• 256

  StriedterG. F.NorthcuttR. G. (2020). Brains Through Time: A Natural History of Vertebrates.London: Oxford University Press.

  • Google Scholar

• 257

  SwansonL. W. (1992). Brain Maps: Structure of the Rat Brain.Amsterdam, London, New York, NY: Elsevier.

  • Google Scholar

• 258

  SwansonL. W. (2012). Brain Architecture: Understanding the Basic Plan.Oxford: Oxford University Press.

  • Google Scholar

• 259

  SzabóN. E.ZhaoT.CankayaM.TheilT.ZhouX.Alvarez-BoladoG. (2009). Role of neuroepithelial sonic hedgehog in hypothalamic patterning. J. Neurosci.29, 6989–7002. 10.1523/JNEUROSCI.1089-09.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  Take-uchiM.ClarkeJ. D.WilsonS. W. (2003). Hedgehog signalling maintains the optic stalk-retinal interface through the regulation of Vax gene activity. Development130, 955–968. 10.1242/dev.00305

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  TakumaN.ShengH. Z.FurutaY.WardJ. M.SharmaK.HoganB. L.et al. (1998). Formation of Rathke’s pouch requires dual induction from the diencephalon. Development125, 4835–4840.

  • Pubmed Abstract
  • Google Scholar

• 262

  ten DonkelaarH. J. (2018). An Illustrated Terminologia Anatomica. A Concise Encyclopedia of Human Neuroanatomy.Berlin: Springer.

  • Google Scholar

• 263

  ten DonkelaarH. J. (2020). Clinical Neuroanatomy.Berlin: Springer.

  • Google Scholar

• 264

  TheilerK. (1989). The House Mouse Atlas of Embryonic Development.New York, NY: Springer Verlag.

  • Google Scholar

• 265

  ThomasP.BeddingtonR. (1996). Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol.6, 1487–1496. 10.1016/s0960-9822(96)00753-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  ThomasP. Q.DattaniM. T.BrickmanJ. M.McNayD.WarneG.ZacharinM.et al. (2001). Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum. Mol. Genet.10, 39–45. 10.1093/hmg/10.1.39

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  TroweM. O.ZhaoL.WeissA. C.ChristoffelsV.EpsteinD. J.KispertA. (2013). Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for formation of the neurohypophysis. Development140, 2299–2309. 10.1242/dev.094524

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  TsaiP. S.BrooksL. R.RochesterJ. R.KavanaughS. I.ChungW. C. (2011). Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus. Front. Neuroendocrinol.32, 95–107. 10.1016/j.yfrne.2010.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  VieiraC.PomberoA.García-LopezR.GimenoL.EchevarriaD.MartínezS. (2010). Molecular mechanisms controlling brain development: an overview of neuroepithelial secondary organizers. Int. J. Dev. Biol.54, 7–20. 10.1387/ijdb.092853cv

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  WallisD.MuenkeM. (2000). Mutations in holoprosencephaly. Hum. Mutat.16, 99–108. 10.1002/1098-1004(200008)16:2<99::AID-HUMU2>3.0.CO;2-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  WalsheJ.MasonI. (2003). Fgf signalling is required for formation of cartilage in the head. Dev. Biol.264, 522–536. 10.1016/j.ydbio.2003.08.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  WangW.LufkinT. (2000). The murine Otp homeobox gene plays an essential role in the specification of neuronal cell lineages in the developing hypothalamus. Dev. Biol.227, 432–449. 10.1006/dbio.2000.9902

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  WatsonC.KircaldieM.PaxinosG. (2010). The Brain. An Introduction to Functional Neuroanatomy.San Diego: Elsevier Academic Press.

  • Google Scholar

• 274

  WebbE. A.DattaniM. T. (2010). Septo-optic dysplasia. Eur. J. Hum. Genet.18, 393–397. 10.1038/ejhg.2009.125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  WehrR.MansouriA.de MaeyerT.GrussP. (1997). Fkh5-deficient mice show dysgenesis in the caudal midbrain and hypothalamic mammillary body. Development124, 4447–4456.

  • Pubmed Abstract
  • Google Scholar

• 276

  WilsonP. A.Hemmati-BrivanlouA. (1995). Induction of epidermis and inhibition of neural fate by Bmp-4. Nature376, 331–333. 10.1038/376331a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  WolpertL. (1969). Positional information and the spatial pattern of cellular differentiation. J. Theor. Biol.25, 1–47. 10.1016/s0022-5193(69)80016-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  WolpertL. (2016). Positional information and pattern formation. Curr. Top. Dev. Biol.117, 597–608. 10.1016/bs.ctdb.2015.11.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  WoodH. B.EpiskopouV. (1999). Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech. Dev.86, 197–201. 10.1016/s0925-4773(99)00116-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  XieY.DorskyR. I. (2017). Development of the hypothalamus: conservation, modification and innovation. Development144, 1588–1599. 10.1242/dev.139055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  YamadaT.PlaczekM.TanakaH.DoddJ.JessellT. M. (1991). Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord. Cell64, 635–647. 10.1016/0092-8674(91)90247-v

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  YamamotoK.BlochS.VernierP. (2017). New perspective on the regionalization of the anterior forebrain in Osteichthyes. Dev. Growth Differ.59, 175–187. 10.1111/dgd.12348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  YeW.ShimamuraK.RubensteinJ. L.HynesM. A.RosenthalA. (1998). FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell93, 755–766. 10.1016/s0092-8674(00)81437-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  YiL.LiuZ.DengC.LiX.WangK.DengK.et al. (2019). Epidemiological characteristics of holoprosencephaly in China, 2007–2014: a retrospective study based on the national birth defects surveillance system. PLoS One14:e0217835. 10.1371/journal.pone.0217835

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  YuZ.SunY.SheX.WangZ.ChenS.DengZ.et al. (2017). SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B. J. Hematol. Oncol.10:115. 10.1186/s13045-017-0483-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  ZhaoT.SzabóN.MaJ.LuoL.ZhouX.Alvarez-BoladoG. (2008). Genetic mapping of Foxb1-cell lineage shows migration from caudal diencephalon to telencephalon and lateral hypothalamus. Eur. J. Neurosci.28, 1941–1955. 10.1111/j.1460-9568.2008.06503.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 287

  ZhaoL.ZevallosS. E.RizzotiK.JeongY.Lovell-BadgeR.EpsteinD. J. (2012). Disruption of SoxB1-dependent Sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia. Dev. Cell22, 585–596. 10.1016/j.devcel.2011.12.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar