The hypothalamic-pituitary-gonadal (HPG) axis is imperative in the control of reproduction in vertebrates. It was thought that gonadotropin-releasing hormone (GnRH) was the only hypothalamic neuropeptide that regulates the HPG axis since its discovery at the beginning of the 1970s (1, 2). However, two new key hypothalamic neuropeptides, i.e., gonadotropin-inhibitory hormone (GnIH) and kisspeptin, have been found in the beginning of the 2000s to play key roles in the control of reproduction (3–6). In 2000, GnIH was discovered in the quail hypothalamus (3). Following intensive researches showed that GnIH inhibits gonadotropin synthesis and release through actions on GnRH neurons and gonadotropes via a G-protein coupled receptor (GPCR), GPR147, in birds and mammals (7). GnIH peptides were also identified in other vertebrate species from fish to humans. As in birds, mammalian and fish GnIH peptides inhibit gonadotropin release, indicating the conserved inhibitory role of GnIH in the regulation of the HPG axis (7). Following the discovery of GnIH, kisspeptin, encoded by the Kiss1 gene, was discovered in mammals. In contrast to GnIH, kisspeptin has a stimulatory effect on GnRH neurons via another GPCR, GPR54 (5, 6). The Kiss1 gene was also identified in amphibians and fish (8). Therefore, we now know that GnRH is not the only hypothalamic neuropeptide controlling reproduction in vertebrates. The aim of this flagship Research Topic is to review the discoveries of GnIH and kisspeptin and the progress in reproductive neuroendocrinology made by these hypothalamic neuropeptides by collecting review articles from leading scientists in this new research field.
The first review article by Tsutsui and Ubuka summarizes the discovery of GnIH and progresses of GnIH research. GnIH was isolated and its structure was determined in 2000 (3). Its function that inhibits gonadotropin release was shown in quail in vitro (3) and in vivo (4). The article introduces that GnIH inhibits gonadotropin synthesis and release from gonadotropes by acting on gonadotropes and GnRH neurons via GPR147 (9, 10). The article also reviews that GnIH acts in the brain to regulate various behaviors (11–13). The second review article by Son et al. describes the molecular mechanisms of GnIH actions in target cells and how GnIH expression is regulated. Based on the morphology of GnIH neuronal fibers and GnIH receptor, GnRH neurons and gonadotropes are the major targets of GnIH action (3, 14–17). It was demonstrated that GnIH inhibits the adenylate cyclase (AC)/cAMP/protein kinase A (PKA)-dependent pathway both in GnRH neurons and gonadotropes (9, 10). The article further summarizes the mechanisms of how GnIH expression is regulated by glucocorticoid (18) and thyroid hormone (19). The third review article by Angelopoulou et al. introduces that RFRP-3, mammalian GnIH, is involved in the central control of daily and seasonal rhythms of reproduction to synchronize reproductive activity to environmental challenges. Melatonin and thyroid hormones may play critical roles in the regulation of GnIH neurons that convey environmental information to GnRH neurons and gonadotropes (17, 20–23). The fourth review article by Tobari and Tsutsui introduces the effects of social information on GnIH in birds (13). The article reviews researches that investigates the changes in the activities of GnIH neuronal system according to social status. The article introduces the pathway after visual perception of a potential mate and the rapid change in gonadotropin levels via the GnIH neuronal system in male birds. The fifth review article by Di Yorio et al. summarizes what are known and unknown about fish GnIH (24, 25). The article emphasizes that teleost is characterized by three round whole genome duplication that could be responsible for the great phenotypic complexity and variability in reproductive strategies and sexual behavior. The fact may also affect the distribution of GnIH cell bodies and fibers and its relationship with GnRH variants. The article proposes that GnIH may have other functions than reproduction or act as an integrator in the reproductive process in teleosts. The last review article by Uenoyama et al. introduces the triggering role of kisspeptin that controls pubertal onset in mammals. Kisspeptin is a potent secretagogue of GnRH secretion therefore its release is fundamental to pubertal increase in GnRH/gonadotropin secretion. It is thought that puberty is timed by an increase in pulsatile GnRH/gonadotropin secretion in mammals. Recent researches suggest that kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in the arcuate nucleus may play an important role in pulsatile GnRH/gonadotropin secretin during pubertal onset (26). The article further suggests that the timing of pubertal onset is controlled by upstream regulators of kisspeptin expression and release.
The review articles collected in this flagship Research Topic acknowledge that GnIH and kisspeptin play important roles in the hypothalamic control of reproduction, which is indispensable in developmental, seasonal, and social regulation of reproductive activities in vertebrates.
Statements
Author contributions
TU wrote the manuscript. KT edited the manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1.
BurgusRButcherMAmossMLingNMonahanMRivierJet al. Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF) (LH-hypothalamus-LRF-gas chromatography-mass spectrometry-decapeptide-Edman degradation). Proc Natl Acad Sci USA. (1972) 69:278–82. 10.1073/pnas.69.1.278
2.
MatsuoHBabaYNairRMArimuraASchallyAV. Structure of the porcineLH- and FSH-releasing hormone. I The proposed amino acid sequence. Biochem Biophys Res Commun. (1971) 43:1334–9. 10.1016/S0006-291X(71)80019-0
3.
TsutsuiKSaigohEUkenaKTeranishiHFujisawaYKikuchiMet al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun. (2000) 275:661–7. 10.1006/bbrc.2000.3350
4.
UbukaTUkenaKSharpPJBentleyGETsutsuiK. Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail. Endocrinology. (2006) 147:1187–94. 10.1210/en.2005-1178
5.
de RouxNGeninECarelJCMatsudaFChaussainJLMilgromE. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. (2003) 100:10972–6. 10.1073/pnas.1834399100
6.
SeminaraSBMessagerSChatzidakiEEThresherRRAciernoJSJrShagouryJKet al. The GPR54 gene as a regulator of puberty. N Engl J Med. (2003) 349:1614–27. 10.1056/NEJMoa035322
7.
UbukaTSonYLTsutsuiK. Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone. Gen Comp Endocrinol. (2016) 227:27–50. 10.1016/j.ygcen.2015.09.009
8.
LeeYRTsunekawaKMoonMJUmHNHwangJIOsugiTet al. Molecular evolution of multiple forms of kisspeptins and GPR54 receptors in vertebrates. Endocrinology. (2009) 150:2837–46. 10.1210/en.2008-1679
9.
SonYLUbukaTMillarRPKanasakiHTsutsuiK. Gonadotropin-inhibitory hormone inhibits GnRH-induced gonadotropin subunit gene transcriptions by inhibiting AC/cAMP/PKA-dependent ERK pathway in LβT2 cells. Endocrinology. (2012) 153:2332–43. 10.1210/en.2011-1904
10.
SonYLUbukaTSogaTYamamotoKBentleyGETsutsuiK. Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7. FASEB J. (2016) 30:2198–210. 10.1096/fj.201500055
11.
UbukaTMukaiMWolfeJBeverlyRCleggSWangAet al. RNA interference of gonadotropin-inhibitory hormone gene induces arousal in songbirds. PLoS ONE. (2012) 7:e30202. 10.1371/journal.pone.0030202
12.
UbukaTHaraguchiSTobariYNarihiroMIshikawaKHayashiTet al. Hypothalamic inhibition of socio-sexual behaviour by increasing neuroestrogen synthesis. Nat Commun. (2014) 5:3061. 10.1038/ncomms4061
13.
TobariYSonYLUbukaTHasegawaYTsutsuiK. A new pathway mediating social effects on the endocrine system: female presence acting via norepinephrine release stimulates gonadotropin-inhibitory hormone in the paraventricular nucleus and suppresses luteinizing hormone in quail. J Neurosci. (2014) 34:9803–11. 10.1523/JNEUROSCI.3706-13.2014
14.
UbukaTKimSHuangYCReidJJiangJOsugiTet al. Gonadotropin-inhibitory hormone neurons interact directly with gonadotropin-releasing hormone-I and -II neurons in European starling brain. Endocrinology. (2008) 149:268–78. 10.1210/en.2007-0983
15.
UbukaTLaiHKitaniMSuzuuchiAPhamVCadiganPAet al. Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain. J Comp Neurol. (2009) 517:841–55. 10.1002/cne.22191
16.
UbukaTMorganKPawsonAJOsugiTChowdhuryVSMinakataHet al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS ONE. (2009) 4:e8400. 10.1371/journal.pone.0008400
17.
UbukaTInoueKFukudaYMizunoTUkenaKKriegsfeldLJet al. Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone. Endocrinology. (2012) 153:373–85. 10.1210/en.2011-1110
18.
SonYLUbukaTNarihiroMFukudaYHasunumaIYamamotoKet al. Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone. Endocrinology. (2014) 155:1817–26. 10.1210/en.2013-2076
19.
KiyoharaMSonYLTsutsuiK. Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status. Sci Rep. (2017) 7:1042. 10.1038/s41598-017-01183-8
20.
UbukaTBentleyGEUkenaKWingfieldJCTsutsuiK. Melatonin induces the expression of gonadotropin-inhibitory hormone in the avian brain. Proc Natl Acad Sci USA. (2005) 102:3052–7. 10.1073/pnas.0403840102
21.
KlosenPBienvenuCDemarteauODardenteHGuerreroHPévetPet al. The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSH-immunoreactive cells in the pars tuberalis of the rat pituitary. J Histochem Cytochem. (2002) 50:1647–57. 10.1177/002215540205001209
22.
DardenteHWyseCABirnieMJDupréSMLoudonASILincolnGAet al. A molecular switch for photoperiod responsiveness in mammals. Curr Biol. (2010) 20:2193–8. 10.1016/j.cub.2010.10.048
23.
KlosenPSébertM-ERasriKLaran-ChichM-PSimonneauxV. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin. FASEB J. (2013) 27:2677–86. 10.1096/fj.13-229559
24.
UbukaTParharI. Dual actions of mammalian and piscine gonadotropin-inhibitory hormones, RFamide-related peptides and LPXRFamide peptides, in the hypothalamic-pituitary-gonadal axis. Front Endocrinol. (2018). 8:377. 10.3389/fendo.2017.00377
25.
Muñoz-CuetoJAPaullada-SalmerónJAAliaga-GuerreroMCowanMEParharISUbukaT. A journey through the gonadotropin-inhibitory hormone system of fish. Front Endocrinol. (2017) 8:285. 10.3389/fendo.2017.00285
26.
IkegamiKMinabeSIedaNGotoTSugimotoANakamuraSet al. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones. J Neuroendocrinol. (2017) 29:1–14. 10.1111/jne.12480
Summary
Keywords
gonadotropin-releasing hormone, gonadotropin-inhibitory hormone, kisspeptin, hypothalamus, pituitary, seasonal reproduction, social information, puberty
Citation
Tsutsui K and Ubuka T (2019) Editorial: Progress in Reproductive Neuroendocrinology in Vertebrates. Front. Endocrinol. 10:895. doi: 10.3389/fendo.2019.00895
Received
28 November 2019
Accepted
06 December 2019
Published
19 December 2019
Volume
10 - 2019
Edited and reviewed by
Cunming Duan, University of Michigan, United States
Updates
Copyright
© 2019 Tsutsui and Ubuka.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kazuyoshi Tsutsui k-tsutsui@waseda.jpTakayoshi Ubuka takayoshi.ubuka@gmail.com
This article was submitted to Experimental Endocrinology, a section of the journal Frontiers in Endocrinology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.