A predominant function of PTPRF is the regulation of the actin cytoskeleton (Sarhan et al., 2016b). It has been observed that PTPRF knockout leads to a reduction in the number of focal adhesions and reduced adhesion to the extracellular matrix, suggesting PTPRF as a part of a complex that links actin cytoskeleton to the extracellular matrix and forms focal adhesions to promote neurite growth (Dunah et al., 2005; Sarhan et al., 2016a). PTPRF interaction with extracellular matrix ligands promote its catalytic activation and the dephosphorylation the tyrosine kinase ABL1, which promotes AKT and CDK1 activation (Sarhan et al., 2016a), increasing cell adhesion to extracellular matrix and favoring the growth of dendrites and axons (Serra-Pagès et al., 1995). Also, PTPRF homophilic interaction with its ectodomain has been shown to promote neurite outgrowth, in a mechanism where the ectodomain acts as a ligand to induce PTPRF phosphatase activity, which then participates in the intracellular activation of several signaling pathways (Yang et al., 2003, 2005).

A role for PTPRD in dendrite growth was discovered in PTPRD knockout mice, which display reduced dendritic branching, length, and thickness (Nakamura et al., 2017). PTPRD promotes dendrite growth by dephosphorylating and activating Fyn and Src kinases, which induces the arborization of dendrites mediated by Semaphorin-3A (Nakamura et al., 2017). Also, Semaphorin-3A-induced growth cone collapse response has been shown to be dependent on PTPRD expression, suggesting direct participation of PTPRD in axon growth (Nakamura et al., 2017). Besides, a soluble gradient of PTPRD induces chemoattraction of growth cones in neuronal cultures, in a mechanism dependent on tyrosine phosphatase activity (Sun et al., 2000), which highlights the dual role of PTPRD as a ligand and as a signaling molecule in axon growth regulation. However, PTPRD knockout mice do not show gross impairment in axon growth, while knocking out both PTPRD and PTPRS induces axon degeneration as peripheral nerves fail to contact their targets (Uetani et al., 2006). This indicates that LAR-RPTPs may have redundant roles in axon growth regulation (Stoker, 2015).

PTPRS has the opposite role in the development of dendrites compared to PTPRF and PTPRD, as PTPRS knockout mice show increased dendritic length in vivo (Horn et al., 2012). The inhibition of dendritic formation mediated by PTPRS depends on its direct interaction with its ligand CSPG, which induces PTPRS-mediated TrkB dephosphorylation, thereby suppressing dendritic spine growth (Figure 3A) (Kurihara and Yamashita, 2012; Lesnikova et al., 2020). Neurite outgrowth inhibition induced by CSPGs also appears to be mediated by the intracellular interaction between PTPRS and the nucleoside diphosphate kinase 2 NME2 (Figure 3A) (Hamasaki et al., 2016).

PTPRS also negatively regulates axon growth, as PTPRS knockout or catalytic inactivation has been widely reported to activate axonal elongation. Interaction with HSPGs ligands induces the formation of PTPRS dimers, which inactivates its phosphatase activity and promotes axon elongation (Figure 3B), while CSPGs engagement promotes the PTPRS monomer conformation, unleashing its catalytic activity and inhibiting growth cone elongation (Coles et al., 2011; Lang, et al., 2015; Shen et al., 2009). Furthermore, embryonic cortical neurons isolated from PTPRS knockout animals showed an increased rate of axonal elongation (Thompson et al., 2003). PTPRS deficient animals also showed significantly accelerated axonal regeneration in facial motor neuron axotomy, sciatic nerve crush injury and spinal hemisection models (McLean et al., 2002; Thompson et al., 2003; Fry et al., 2009). The same results were observed when axonal regeneration was evaluated after optic nerve injury, where the number of axons that cross the lesion site was higher in PTPRS deficient mice (Sapieha et al., 2005). Besides, mice lacking PTPRS also show increased axon collateral branching in the hippocampus during normal aging or following chemically induced seizure (Horn et al., 2012), suggesting that PTPRS has an important role in maintaining neuronal structures by suppressing dendritic formation, and axonal growth and branching. Also, catalytic inhibition of PTPRS using a wedge motif peptide-mimetic efficiently restores axonal elongation in mice models of spinal cord injury, recovering the serotoninergic innervation into the spinal cord (Lang et al., 2015). Therefore, PTPRS may be a promising therapeutic target for axonal degeneration pathologies.

N-cadherin and β-catenin have been proposed as the substrates that mediates PTPRS participation in the inhibition of axonal growth. The dephosphorylation of N-cadherin and β-catenin by PTPRS promotes N-cadherin-β-catenin complex formation, which favors the association between N-cadherin and the actin cytoskeleton to reduce axonal growth (Figure 3C) (Siu et al., 2007). Another substrate proposed to interact with PTPRS is p250GAP (Chagnon et al., 2010), a GTPase-activating protein that regulate the small GTPases RhoA, Rac and Cdc42 (Moon and Zheng, 2003; Nakazawa et al., 2003). This protein is widely expressed in the embryonic and adult brain with an expression pattern similar to PTPRS (Schaapveld et al., 1998; Simó and Cooper, 2012). Neuronal cultures obtained from p250GAP deficient animals presented longer neurites compared to wild-type mice (Simó and Cooper, 2012), a phenotype similar to PTPRS-deficient neuronal cultures (Thompson et al., 2003), suggesting that p250GAP and PTPRS could be acting in the same pathway. As the activity of p250GAP increases in the presence of PTPRS (Chagnon et al., 2010), and its activity is inhibited by phosphorylation (Okabe et al., 2003), p250GAP dephosphorylation and activation mediated by PTPRS could therefore be important to restrict neurite outgrowth.

The participation of LAR-RPTPs in several signaling pathways that regulate neurite outgrowth and axon guidance reveals important roles of LAR-RPTPs to ensure correct brain development. However, a recent paper has disputed the participation of LAR-RPTPs in the regulation of neuronal morphology. Sclip and Südhof (2020) have found that knocking out LAR-RPTP expression after neurogenesis but before synapse formation do not affect dendritic and axonal growth, which was observed when the genes encoding all three LAR-RPTPs, singly or in combination, were deleted in cultured neurons, suggesting that LAR-RPTPs expression is expendable for neuronal development, at least in hippocampal neurons (Sclip and Südhof, 2020). These results, which contradict the evidence summarized above, suggest that functions of LAR-RPTPs in neuronal development needs to be revisited, and highlights the importance of studying the role of LAR-RPTPs in the brain considering factors such as cellular context and developmental stage (Tomita et al., 2020).

Presynaptic PTPRF participates indirectly in LTD through its interaction with netrin-G ligand-3 (NGL-3) when promotes synaptic differentiation (Woo et al., 2009; Kwon et al., 2010). Treatment with NMDA in cultured neurons or low-frequency stimulation in brain slices induces the proteolytic cleavage of NGL-3, which disrupts the trans-synaptic interaction between NGL-3 and PTPRF, impairing synaptic adhesion during LTD, and weakening excitatory synapses (Lee et al., 2014).

PTPRD knockout mice show enhanced long-term potentiation (LTP) in hippocampal synapses, possibly due to increased neurotransmitter release in the CA1 region. This induces behavioral alterations such as impaired spatial learning and memory, and motor deficits (Uetani et al., 2000), illustrating the importance of PTPRD for hippocampal LTP formation. However, it has also been shown that PTPRD knockout mice have impaired locomotive behaviors and motor weakness, as well as a transient delay in myelination at early postnatal development (Drgonova and Walther, 2015; Zhu et al., 2015), which could partially explain their altered behavior observed in learning tests. PTPRD knockout mice also have impaired synaptic development and decreased excitatory synaptic transmission mainly due to the dysfunction in its interaction with IL1RAPL1 (Park et al., 2020), which highlights the role of PTPRD not only in synaptic formation, but also in excitatory neurotransmission. In contrast, a recent study using pan-neuronal PTPRD conditional knockout animals, showed that PTPRD is not essential for maintenance of excitatory or inhibitory synaptic transmission, since absence of PTPRD did not modify synaptic parameters such as the number of excitatory or inhibitory synapses, miniature excitatory postsynaptic currents (mEPSC), synaptic vesicle tethering, active zone modifications nor neurotransmitter release (Han et al., 2020c), suggesting that PTPRD does not play a significant role in these neurobiological processes. It is important to highlight that Park et al. (2020) found that interaction between PTPRD and IL1RAPL1 is dependent on PTPRD alternative splicing. As much of the signaling mediated by PTPRD depends on interaction with specific ligands, different alternative splicing variants might participate in different cellular processes. Therefore, the controversial results observed in recent studies should be analyzed cautiously, as different alternatively spliced isoforms of PTPRD could generate different neuronal outcomes.

In presynaptic terminals, PTPRS has been shown to participate in excitatory synaptic function by regulating the localization and size of excitatory synaptic vesicles, modulating glutamate release in the hippocampus, and it also seems to regulate structural features of the active zone such as its length, suggesting that PTPRS participates in the molecular organization of the active zone machinery to efficiently promote glutamate release (Han et al., 2020b). PTPRS is also implicated in regulation of the postsynaptic excitatory neurotransmission. PTPRS interacts with GPC-4 and LRRTM4 to regulate frequency and amplitude of excitatory synaptic transmission. Studies in cultured hippocampal neurons showed that PTPRS knockdown decreased the frequency and amplitude of mEPSC, an effect that was reversed by re-expression of wild-type PTPRS, but not by heparan sulfate (HS)-binding-defective PTPRS mutant that impairs its interaction with GPC-4 and LRRTM4. These observations suggest that PTPRS-GPC-4-LRRTM4 interaction has an important role in the maintenance and function of excitatory synapses (Ko et al., 2015). However, these results contradict previous findings, where mice lacking PTPRS showed increased frequency of mEPSC, which resulted in reduced LTP, and greater paired-pulse facilitation (Horn et al., 2012). One possible explanation could be differential roles for PTPRS splice variants. As in the case of PTPRD, the different synaptic functions in which PTPRS participates must be carefully studied considering the different splicing isoforms, as the interaction of PTPRS with its ligands also depends on alternative splicing (Han et al., 2020a). Recent studies have proposed possible mechanisms by which PTPRS regulates excitatory synapses in the hippocampus (Kim et al., 2020; Sclip and Südhof, 2020). These studies strongly suggest that presynaptic PTPRS promotes LTP through its regulation of NMDAR in the postsynaptic. This is supported by results showing that postsynaptic deletion of PTPRS or the deletion of its extracellular regions required for trans-synaptic adhesions do not affect LTP, and therefore PTPRS ligand binding activity would be expendable for NMDAR regulation (Kim et al., 2020). It was also observed that PTPRS catalytic activity mediates dephosphorylation of presynaptic Neurexin-1, which interacts with PTPRS though a complex with liprin-α among others (Serra-Pagès et al., 1995; Hata et al., 1996; Olsen et al., 2005; Weng et al., 2011; Bomkamp et al., 2019), to promote NMDAR-mediated postsynaptic activity (Dai et al., 2019; Kim et al., 2020). These results suggest a mechanism mediated by PTPRS-neurexin-1 presynaptic intracellular complex that regulates NMDAR postsynaptic activation and LTP induction, which is important for recognition memory and novelty preference (Kim et al., 2020). This finding correlates with results obtained by Sclip and Südhof (2020), where a triple conditional knockout mouse for all three LAR-RPTPs show a decrease in NMDAR-mEPSCs in the hippocampus, which is due to a reduction in NMDAR postsynaptic location and not to NMDAR protein levels (Sclip and Südhof, 2020).

The evidence summarized here shows that LAR-RPTP interactions with trans-synaptic ligands and with their intracellular substrates modulates a series of synaptic processes required for neuronal function. Even though recent papers have questioned LAR-RPTP participation in some of these biological processes, several evidence showing a primary role in synaptic formation suggest that LAR-RPTP functions can not be underestimated, and more studies are needed to unravel the differential roles that LAR-RPTP alternative splicing variants might have over these neuronal functions.

The first molecule discovered to interact trans-synaptically with all three LAR-RPTPs was NGL-3, a synaptic adhesion molecule involved in synaptic formation and neurotransmission (Kwon et al., 2010; Woo et al., 2009). Interaction between PTPRF and PTPRS with NGL-3 induces pre and postsynaptic differentiation when contacting axons and dendrites respectively, forming a trans-synaptic complex that induces bidirectional excitatory synaptic formation (Kwon et al., 2010; Woo et al., 2009). Presynaptic PTPRF and PTPRS interact with postsynaptic NGL-3 to promote excitatory postsynaptic differentiation, which is mediated by the direct interaction between NGL-3 and PSD-95 (Kwon et al., 2010). PTPRD also interacts with NGL-3 to promote excitatory differentiation, but in a unidirectional manner. Therefore, PTPRD appears to be the only LAR-RPTP unable to induce PSD-95 recruitment and postsynaptic differentiation when interacting with NGL-3 (Kwon et al., 2010). All three LAR-RPTPs also interact with SALM3 and SALM5, members of the SALM family of cell adhesion-like proteins that modulate differentiation, maintenance, and plasticity of the synapse (Ko et al., 2006), and their interaction with LAR-RPTPs promotes excitatory synapse development (Choi et al., 2016; Li et al., 2015; Lie et al., 2016). The interaction between LAR-RPTPs and SALM3 synaptic differentiation is apparently induced in a bidirectional manner, since SALM3 binding to each LAR-RPTP recruits excitatory presynaptic proteins (Li et al., 2015), and aggregation of SALM3 on dendritic surfaces induces clustering of PSD-95 (Mah et al., 2010). Interaction between SALM3 and LAR-RPTPs can be inhibited by the cis-interaction of SALM3 and SALM4, and therefore this interaction induces an inhibition of the SALM3-dependent excitatory presynaptic differentiation (Lie et al., 2016). On the other hand, the interaction between LAR-RPTPs and SALM5 induces unidirectional presynaptic differentiation due to lack of a PDZ-binding motif necessary to interact with PSD-95 in the postsynaptic (Choi et al., 2016; Goto-Ito et al., 2018; Mah et al., 2010).

Besides NGL-3 and SALM3/5, a PTPRF cis-interaction with netrin-G1 has been observed, which can also induce excitatory differentiation in a unidirectional manner. Presynaptic netrin-G1 interacts with postsynaptic netrin-G ligand-1 (NGL-1), and simultaneously directly interacts with adjacent PTPRF to shape pre-synaptic excitatory synapsis (Song et al., 2013). However, it remains to be confirmed if this interaction also occurs in vivo.

PTPRD is the only LAR-RPTP whose expression has been observed in both excitatory and inhibitory synapses, where its interaction with NGL-3, SALM3/5, IL1RAPL1 and IL1RAcP induce excitatory differentiation, while its interaction with Slitrk1, Slitrk2 and Slitrk3 induce inhibitory synaptic differentiation (Goto-Ito et al., 2018; Kwon et al., 2010; Li et al., 2015; Lin et al., 2018; Park et al., 2020; Takahashi et al., 2012; Valnegri et al., 2011; Yim et al., 2013; Yoshida et al., 2011; Yoshida et al., 2012). Axonal PTPRD induces excitatory synaptic development bidirectionally through the interaction with its postsynaptic ligand IL1RAPL1 (Valnegri et al., 2011; Yoshida et al., 2011; Park et al., 2020). PTPRD-IL1RAPL1 interaction recruits RhoGTPase-activating protein 2 (RhoGAP2) in the post-synaptic density which promotes a signaling pathway that favors excitatory synapse development and dendritic spine formation (Valnegri et al., 2011; Park et al., 2020). Also, the postsynaptic excitatory differentiation induced by the interaction of PTPRD and IL1RAPL1 depend on the modulation of c-Jun terminal kinase (JNK) signaling pathway, since PTPRD activates IL1RAPL1, inducing JNK activation, which phosphorylates PSD-95 and promotes its synaptic clustering (Pavlowsky et al., 2010; Park et al., 2020). However, whether RhoGAP2 participates in JNK-mediated synaptic differentiation has not been clarified. Also, PTPRD interacts with a brain isoform of IL1RAcP, a protein essential for immune response, which promotes excitatory synaptic differentiation bidirectionally (Yoshida et al., 2012; Yamagata et al., 2015). Although IL1RAcP has homology to IL1RAPL1, it is not known whether they share a common mechanism for PTPRD-mediated synaptic differentiation. Slitrk1/2/3 are also synaptic partners for PTPRD, and their interaction induces inhibitory synapse development in a unidirectional manner, since the complex induces a presynaptic GABAergic synapse differentiation, without necessarily shaping the postsynaptic (Takahashi et al., 2012; Yim et al., 2013).

Recently, a study has identified Neuroligin3 (NLGN3) as a new ligand for PTPRD. This interaction induces excitatory or inhibitory post-synaptic differentiation depending on micro-exon meB inclusion (Yoshida et al., 2021). Furthermore, it was also observed that PTPRD and NLGN3 mediate social behaviors such as social preference and negative social response and regulate excitatory/inhibitory synaptic differentiation (Yoshida et al., 2021), highlighting the role of PTPRD splicing and its isoform interactions in excitatory/inhibitory balance.

TrkC is one of the major postsynaptic partners for PTPRS, and their trans-synaptic interaction generates the development of excitatory synapse in a bidirectional manner (Takahashi et al., 2011; Han et al., 2018), where this complex recruits synapsin (mediated by the D2 domain of PTPRS) in the presynaptic and PSD-95 at the postsynaptic (Takahashi et al., 2011). Also, TrkC competes with HS for PTPRS interaction. HS-bound PTPRS molecules tend to assemble as oligomers at the presynaptic membrane, which inactivates its catalytic activity and promotes axon growth, whilst unbound PTPRS monomers tend to interact with TrkC to induce synaptic differentiation (Coles et al., 2011; Won et al., 2017; Han et al., 2018; Han et al., 2020a). Therefore, PTPRS interaction with both ligands and its consequent participation in each cellular process must be tightly regulated, suggesting the existence of an undefined developmental mechanism to switch PTPRS functions. When oligomeric PTPRS interacts with HS, it forms a cis-complexes with glypican-4 (GPC-4) with high affinity (Ko et al., 2015). GPC-4 also interacts with the postsynaptic molecule LRRTM4, which induces a bidirectional excitatory synaptic differentiation mediated by PTPRS-GPC-4-LRRTM4 complex formation, and where presynaptic differentiation depends on the PTPRS catalytic activation induced by GPC-4 binding (Ko et al., 2015; Roppongi et al., 2020). This mechanism is developmentally regulated, since PTPRS only interacts with cleaved GPC-4, and its proteolytic cleavage is reduced during postnatal development (Ko et al., 2015). On the other hand, it has been observed that LRRTM4-mediated synaptic differentiation is also dependent on PTPRS cis interaction with HS chains of Neurexins, where PTPRS-Neurexin-LRRTM4 and PTPRS-GPC-4-LRRTM4 complexes would coexist independently to induce the same process (Roppongi et al., 2020). However, a recent study has suggested that PTPRS cis interaction with HS chains of Neurexins would have an antagonistic role in synaptic differentiation. In mouse cultured hippocampal neurons, the interaction between PTPRS and HS chains of Neurexin1α inhibited excitatory post-synaptic differentiation (Han et al., 2020a). It is important to highlight that HS binding to PTPRS is mediated through Ig like domains and its affinity is highly dependent on PTPRS alternative splicing (Han et al., 2020a). Therefore, synaptic differentiation mediated by PTPRS should be carefully addressed since PTPRS splice variants might modulate differential synaptic pathways even when interacting with the same ligand. Presynaptic PTPRS interacts with Slitrks 1, 2, 4, 5 and 6 through the Ig domains to coordinate the development of the excitatory synapse in a unidirectional manner (Yim et al., 2013; Han et al., 2018). Slitrks-mediated presynaptic differentiation depends on the direct interaction between liprin-α and the PTPRS D2 domain, and also on the recruitment of the presynaptic proteins p250GAP and N-cadherin (Han et al., 2018), showing that PTPRS binding to Slitrks ligands promotes the intracellular assembly of a complex presynaptic differentiation machinery.

Since the interaction of LAR-RPTPs with their synaptic partners controls the formation of excitatory and inhibitory synapses, with profound consequences for the development of the brain, their expression must be regulated in a highly coordinated manner during neurodevelopment. Although the mechanisms involved in the cell-specific expression of LAR-RPTPs and their synaptic partners are unknown, it is possible to suggest that those neurodevelopmental disorders in which the balance between excitatory and inhibitory synapses is lost may be due at least in part to dysregulations in the mechanisms that control the expression of LAR-RPTPs (Nelson and Valakh, 2015; Parenti et al., 2020; Yoshida et al., 2021).

PTPRF knockout mice display increased proliferation in embryonic hippocampal neural precursor cells (NPCs) in vitro and in adult hippocampal NPCs in vivo, which is associated with an increased hippocampal neurogenesis in the adult mouse brain (Bernabeu et al., 2006), although the mechanism for PTPRF neurogenic regulation has not yet been characterized.

Recently, our group found that PTPRD knockout mice have impaired neuronal differentiation and neuronal localization in the brain cortex (Tomita et al., 2020). First, we observed that the PTPRD heterozygous or homozygous knockout mice display increased neuronal intermediate progenitor cells (Tbr2 positive) without changing radial glial cell numbers (Pax6 positive). Also, the intermediate progenitor cells are highly proliferative, resulting in an increased number of differentiated cortical neurons and mislocalization of Satb2 and Tbr1-positive neurons into their corresponding cortical layers. These effects seem to be dependent on PTPRD catalytic activity and its interaction with the neurogenesis-associated receptor tyrosine kinases TrkB and PDGFRβ. Indeed, PTPRD deletion increases phosphorylation of both receptors and downstream kinase effectors MEK1 and ERK1/2 (Figure 5). Furthermore, in vitro inhibition of this signaling pathway by either pharmacological or RNAi strategies rescues neurogenic impairments observed in the absence of PTPRD (Tomita et al., 2020), providing a direct link between PTPRD mutations and neurodevelopmental disorders. However, it is important to highlight that considering differential expression of PTPRD in a variety of neural cell populations and elucidating how PTPRD controls receptor tyrosine kinases will be key for determining the mechanisms by which PTPRD regulates these biological processes during embryonic cortical development.

In the spinal cord, it has been observed that PTPRF and PTPRS interaction with CSPGs inhibits NPC growth, attachment, survival, proliferation, and oligodendrocyte differentiation from NPCs (Dyck et al., 2015). Although the participation of PTPRF and PTPRS in NPC biology and neurodevelopment have not yet been characterized in the brain, NPCs cultured from the subventricular zone of PTPRS knockout mice show increased cellular migration from the neurosphere center, (Kirkham et al., 2006), suggesting a role of PTPRS in controlling NPC migration. In addition, mice lacking PTPRS expression show several neurological defects such as reduced number of choline acetyl transferase (ChAT)-positive neurons, slower nerve conduction velocity as a consequence of smaller myelinated fibers and hypomyelination, accompanied by behavioral alterations such as spastic movements, tremor and abnormal limb flexion among others. This suggests a role for PTPRS in the differentiation and/or development of cholinergic neurons and glial cells (Wallace et al., 1999). In addition, these mice showed deficits in the formation of the pituitary, with an elongated intermediate lobe, and smaller anterior and posterior lobes. This is accompanied by an overall decrease in brain size, a smaller olfactory bulb, and a severe depletion of luteinizing hormone-releasing-positive cells associated to a reduced size of the hypothalamus (Elchebly et al., 1999), suggesting a role for PTPRS in the development of neural cells in some brain areas including the hypothalamus-pituitary axis.

The evidence summarized in this section shows that LAR-RPTPs participate in the regulation of NPCs proliferation, neural differentiation, and neuronal migration, showing an important role in brain development, and their potential participation in the etiology of some neurodevelopmental disorders due to their impaired expression. However, the role of LAR-RPTPs in neurodevelopment remains an understudied field since LAR-RPTP ligands and substrates that participate in brain development have not been fully characterized.

Decreased expression of PTPRF has been observed in induced pluripotent stem cells (iPSCs) obtained from Huntington’s disease (HD) patients, which could have a role in some pathological features of this diseases, such as neural dysfunction and cell death (The HD iPSC Consortium, 2012). In this study, it was observed that HD iPSCs showed significantly less binding to the actin cytoskeleton compared to control iPSCs, in addition to showing cell-cell adhesion deficits in culture. The loss of PTPRF phosphatase activity has previously been associated with a decrease in focal adhesions (Sarhan et al., 2016a), which could affect the interaction of the actin cytoskeleton with the extracellular proteins (Wehrle-Haller, 2012). Therefore, the decrease in actin stability and increased actin dynamics in HD iPSC could be the result of reduced number of focal adhesions. Although it is not known if the reduced expression of PTPRF in HD could have a causative role for this disorder, it might be contributing to the progression of the disease by impairing the ability of neural cells to survive and differentiate in a correct way as a result of alterations in cell adhesion. In neuronal ceroid lipofuscinoses (NCL), a neurodegenerative disorder characterized by blindness, dementia and cortical atrophy, the absence of the soluble lysosomal palmitoylthioesterases Cln1 and Cln5, induces a significant reduction in the expression of PTRPF. Cortical transcription profiles of Cln1 and Cln5 deficient animals revealed profound alterations in genes related to protein phosphorylation that affect the dynamics of the cytoskeleton and neuronal growth cones. Intermediary proteins of these signaling pathways also showed an altered subcellular distribution in culture and brain tissue assays. Although the impairment of genes that control the balance of cytoskeletal dynamics such as PTPRF are not the only cause of NCL, they prove to be important components that contribute to the pathogenesis behind neurodegeneration (von Schantz et al., 2008). Also, in immune-mediated demyelinating diseases, PTPRF expression is upregulated in exosomes obtained from patient cerebrospinal fluid, which is associated with the development of demyelinating diseases, and has been proposed as a biomarker for its early diagnosis (He et al., 2019).

PTPRF deficient mice have been developed to study PTPRF dysfunction. It has been observed that PTPRF knockout animals have a reduced number of cholinergic neurons in the forebrain and a reduced innervation of this cells to the hippocampus, an effect that was also observed in mice lacking PTPRF intracellular domain (Yeo et al., 1997; Van Lieshout et al., 2001). PTPRF deficiency also leads to a behavioral phenotype including induced spatial learning impairments and hyperactivity (Kolkman et al., 2004). Bernabeu and colleagues (2006) also showed that mice lacking PTPRF expression have an increased neurogenesis and increased NPC proliferation in the adult hippocampus (Bernabeu et al., 2006), suggesting a differential role for PTPRF in the forebrain and the hippocampus. Also, PTPRF knockout mice show reduced regenerative and collateral axonal sprouting in peripheral nerves and the forebrain (Van der Zee et al., 2003), and developmental impairments in the mammary gland cells, urogenital malformations, and an impaired craniofacial morphogenesis (Schaapveld et al., 1997; Uetani et al., 2009; Stewart et al., 2013). These animal model studies suggest an important role for PTPRF in the basal forebrain cholinergic signaling, hippocampal neurogenesis, axonal regeneration, and stem cell differentiation.

PTPRD mutations have been directly related to neurological disorders such as restless legs syndrome (RLS) (Schormair et al., 2008; Winkelmann et al., 2011; Yang et al., 2011), obsessive-compulsive disorder (OCD) (Mattheisen et al., 2015; Gazzellone et al., 2016), autism spectrum disorders (ASDs) (Pinto et al., 2010; Levy et al., 2011; Gai et al., 2012; Liu et al., 2016; Ji et al., 2021), attention deficit and hyperactivity disorder (ADHD) (Elia et al., 2010), schizophrenia (Li et al., 2018), intellectual disabilities (Choucair et al., 2015), bipolar disorder (Malhotra et al., 2011), addictions (Drgon et al., 2010; Johnson et al., 2008; Uhl et al., 2008a; Uhl et al., 2008b; Uhl et al., 2010), and tauopathies such as Alzheimer’s disease (AD) (Chibnik et al., 2018). The main PTPRD genetic alterations observed in patients have been summarized in Table 2.

One of the brain disorders in which PTPRD mutations have an important functional impact is RLS, also known as Willis–Ekbom disorder, which is characterized by symptoms including an urge to move, usually accompanied by uncomfortable sensations in the lower limbs (Schormair et al., 2008). The etiology has not yet been determined but may be related to dopaminergic and iron imbalance (Allen, 2004). The relationship between PTPRD and RLS has been established by genome wide association studies (GWAS), where single nucleotide polymorphisms (SNPs) frequently lead to reduced PTPRD mRNA expression (Drgonova and Walther, 2015; Hawrylycz et al., 2012). It is important to note that RLS is effectively treated with dopamine agonists and GABA analogs (Nagandla and De, 2013), although whether PTPRD mutations impair dopaminergic neurotransmission remains unclear.

In OCD, a psychiatric disorder characterized by compulsive behaviors that patients perform in response to obsessive thoughts, PTPRD variants have been associated with this disorder in two GWAS studies. These include a SNP 1.28 Mb from 5′ end of PTPRD gene (Mattheisen et al., 2015), and copy number variants (CNVs) arising from a duplication of 1.5 Mb at 9p24.1 (Gazzellone et al., 2016). Although there is no information on how these variants affect the expression of PTPRD, mouse models deficient for PTPRD show impairments in learning and memory tasks (Uetani et al., 2000), which is relevant for OCD, since memory impairments have been previously reported in OCD patients (Jaafari et al., 2013). Interestingly, PTPRD duplications may also contribute to the development of neurological disorders. It has been observed that duplication (71391bp) of the PTPRD gene at 9p23 has been related to an increased risk of suffering bipolar disorder (Malhotra et al., 2011), suggesting that increased PTPRD expression could also be involved in brain pathologies.

In brain disorders such as ASD, ADHD and intellectual disability, CNVs or mutations in the PTPRD gene (Elia et al., 2010; Pinto et al., 2010; Levy et al., 2011; Choucair et al., 2015) are directly associated with neurodevelopmental impairments. This is consistent with the phenotype of PTPRD knockout mice, which show impaired neuronal differentiation and disrupted cortical organization (Tomita et al., 2020). These mice also display reduced IL1RAPL1-mediated synapse formation (Yoshida et al., 2011), presumably because PTPRD knockout induces a significant reduction in IL1RAPL1 expression (Choucair et al., 2015; Park et al., 2020). Furthermore, specific mutation of the PTPRD IL1RAPL1-interacting domain induces hyperactivity and sleep disturbance, which is also observed in PTPRD conditional knockout mice (Park et al., 2020). Finally, PTPRD knockout mice show body growth retardation and spatial learning and memory impairments, which surprisingly correlates with an enhanced synaptic transmission in the hippocampus (Uetani et al., 2000).

In AD, an SNP in the PTPRD locus shows a mild association with disease, but significant association with accumulation of neurofibrillary tangles (Chibnik et al., 2018). This may be induced by increased levels of phosphorylated tau protein in a PTPRD dependent mechanism, since its participation in tau phosphorylation signaling pathway has been previously suggested (Mitchell et al., 2016), and impaired PTPRD catalytic activity or expression could reduce tau dephosphorylation, although this hypothesis has not yet been tested.

Although no brain pathologies have been causally linked to PTPRS mutations or impaired function, in a rat model of Amyotrophic lateral sclerosis (ALS), reduced neuronal expression of PTPRS has been observed. This may inhibit axonal regeneration and favor glial scar formation through its interaction with CSPGs (Ohtake and Li, 2015; Shijo et al., 2018). Also, PTPRS has recently been considered as a potential target for AD treatment (Gu et al., 2016). PTPRS interacts with amyloid precursor protein (APP) in the brain, and by knocking PTPRS expression, the affinity between β-secretase and APP can be reduced, decreasing Aβ extracellular accumulation and inhibiting tau aggregation without affecting β-secretase enzymatic activity. Moreover, PTPRS knockout rescues behavioral impairments observed in an AD mice model (Gu et al., 2016). This suggests PTPRS as a potential target for selective pharmacological intervention in AD.

As mentioned earlier, mice lacking PTPRS expression show body growth retardation, an abnormal physiology of the posterior pituitary, reduced hormone-releasing cells in the hypothalamus and reduced cholinergic neurons in the forebrain, which associates with neurological impairments such as spastic movements, tremor, ataxic gait, abnormal limb flexion and defective proprioception (Elchebly et al., 1999; Wallace et al., 1999). Moreover, PTPRS knockout mouse show an atypical hippocampus morphology, and a reduced thickness in the corpus callosum and brain cortex, which is suggested to be a consequence of a delayed neurodevelopment and an abnormal NPCs biology (Meathrel et al., 2002; Kirkham et al., 2006). On the other hand, Horn and colleagues (2012) have observed that PTRPS knockout mice show increased dendritic spine density and length, increased frequency of mEPSC, a greater paired-pulse facilitation, and a reduced long-term potentiation in the hippocampus, which correlates with an increased recognition memory, assessed by the novel object recognition test (Horn et al., 2012).

The spectrum of brain disorders involving LAR-RPTPs becomes wider when we consider that their functions in neural cells depend on their interactions. LAR-RPTP synaptic partners such as Slitrks, TrkC and IL1RAPL1, have also been implicated in neurological disorders (Um and Ko, 2013). For instance, Slitrk mutations have been associated with Tourette’s syndrome, trichotillomania, schizophrenia, ASD and epilepsy (Piton et al., 2011; Wu et al., 2013). TrkC mutations have been found in patients with AD, depression, bipolar disorder, and ADHD (Otnæss et al., 2009; Amador-Arjona et al., 2010). IL1RAPL1 has been related to a form of X-linked intellectual disability (Behnecke et al., 2011; Youngs et al., 2012). Hence, the links between LAR-RPTP impairments and the development of neurological disorders, combined with the evidence associating impairments in the LAR-RPTPs synaptic partners with neuronal pathologies, open a wide spectrum of brain disorders where LAR-RPTPs may be either directly or indirectly related. Finally, it is important to highlight that, impairments in the regulation of LAR-RPTP alternative splicing also induce psychiatric disorders. Neuronal micro-exons in LAR-RPTPs are dysregulated in brain samples from patients with ASD, suggesting that disruption of a coordinated program of LAR-RPTP splicing events may lead to neurodevelopmental pathologies (Irimia et al., 2014; Quesnel-Vallières et al., 2015). Therefore, the manipulation of alternative splicing machinery could be used as a therapeutical approach to restore the impaired neural development and the inhibitory/excitatory imbalance observed in neurodevelopmental pathologies such as ASD (Nelson and Valakh, 2015; Parenti et al., 2020; Yoshida et al., 2021).

In summary, LAR-RPTPs are implicated in a variety of neurodevelopmental and neurological dysfunctions, and their mutations and impaired expression is associated with cognitive impairment to dementia. Further studies are necessary to understand how LAR-RPTP genetic variants can contribute to generate diverse brain pathologies. Considering that LAR-RPTPs encode extracellular interaction and intracellular catalytic and regulatory domains, variants in these regions may have diverse impact on neurobiology. Moreover, LAR-RPTPs alternative splicing variants are dependent on extremely short sequences (micro-exons), and SNPs in these critical regions could have profound consequences on LAR-RPTP neurological functions. For example, in the case of LAR-RPTP contributions to synaptic differentiation and function, even subtle genetic alterations could impair interactions with synaptic interaction partners, directly affecting the number of excitatory or inhibitory synapses. Thus, LAR-RPTP genetic variants may contribute in myriad ways to neurological processes that are disrupted in various neuropsychiatric disorders.