Kalirin and Trio: RhoGEFs in Synaptic Transmission, Plasticity, and Complex Brain Disorders
2020; Elsevier BV; Volume: 43; Issue: 7 Linguagem: Inglês
10.1016/j.tins.2020.05.002
ISSN1878-108X
AutoresJeremiah D. Paskus, Bruce E. Herring, Katherine W. Roche,
Tópico(s)Mitochondrial Function and Pathology
ResumoThe synaptic RhoGEFs Kalirin and Trio are paralog proteins that have shared and distinct functions in neuronal development and in synaptic plasticity. Recent phylogenetic analyses have provided resolution surrounding the evolution of these related genes. The retention of both Trio and Kalrn in an organism is concomitant with an increase in Kalirin and Trio isoforms. This proteomic diversity and differential expression is an essential feature of their subfunctionalization, which mediates their distinct and conserved functions.Kalirin and Trio are present at the pre- and postsynaptic sites, and exert their effects on glutamatergic neurotransmission through their ability to regulate the actin cytoskeleton at these synapses.Kalirin-7 is a downstream effector of many postsynaptic adhesion molecules. Such findings implicate Kalirin and possibly Trio as major signaling hubs that regulate glutamatergic synapse development and function.Human genetics studies have identified TRIO as a risk gene in both ASD and schizophrenia. In animal models, ASD-related mutations in TRIO have been found to produce marked alterations in glutamatergic synapse function. Changes in the actin cytoskeleton are a primary mechanism mediating the morphological and functional plasticity that underlies learning and memory. The synaptic Ras homologous (Rho) guanine nucleotide exchange factors (GEFs) Kalirin and Trio have emerged as central regulators of actin dynamics at the synapse. The increased attention surrounding Kalirin and Trio stems from the growing evidence for their roles in the etiology of a wide range of neurodevelopmental and neurodegenerative disorders. In this Review, we discuss recent findings revealing the unique and diverse functions of these paralog proteins in neurodevelopment, excitatory synaptic transmission, and plasticity. We additionally survey the growing literature implicating these proteins in various neurological disorders. Changes in the actin cytoskeleton are a primary mechanism mediating the morphological and functional plasticity that underlies learning and memory. The synaptic Ras homologous (Rho) guanine nucleotide exchange factors (GEFs) Kalirin and Trio have emerged as central regulators of actin dynamics at the synapse. The increased attention surrounding Kalirin and Trio stems from the growing evidence for their roles in the etiology of a wide range of neurodevelopmental and neurodegenerative disorders. In this Review, we discuss recent findings revealing the unique and diverse functions of these paralog proteins in neurodevelopment, excitatory synaptic transmission, and plasticity. We additionally survey the growing literature implicating these proteins in various neurological disorders. GTPases are enzymes that bind GTP, hydrolyzing it to GDP. Different conformational states act to limit GTPase activity [1.Schmidt A. Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch.Genes Dev. 2002; 16: 1587-1609Crossref PubMed Scopus (907) Google Scholar]. These molecular switches function as signal transducers, regulating numerous cellular processes [2.Wennerberg K. et al.The Ras superfamily at a glance.J. Cell Sci. 2005; 118: 843-846Crossref PubMed Scopus (788) Google Scholar]. The Ras superfamily of small GTPases comprises more than 150 members functioning as monomeric G proteins [2.Wennerberg K. et al.The Ras superfamily at a glance.J. Cell Sci. 2005; 118: 843-846Crossref PubMed Scopus (788) Google Scholar]. The Rho family of small GTPases is a major branch of the Ras superfamily. Rho GTPases are regulators of actin dynamics, with Ras-related C3 botulinum toxin substrate 1 (Rac1), Ras homolog family member A (RhoA), and cell division control protein 42 homolog (Cdc42) being the most well-known [3.Etienne-Manneville S. Hall A. Rho GTPases in cell biology.Nature. 2002; 420: 629-635Crossref PubMed Scopus (3488) Google Scholar,4.Nowak J.M. et al.The Rho protein family and its role in the cellular cytoskeleton.Postepy Hig. Med. Dosw. (Online). 2008; 62: 110-117PubMed Google Scholar]. Structural changes in the actin cytoskeleton associated with synaptic plasticity involve Rho family GTPases through their regulation of actin polymerization, resulting in changes in spine morphology [5.Ridley A.J. Rho family proteins: coordinating cell responses.Trends Cell Biol. 2001; 11: 471-477Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar,6.Ba W. Nadif Kasri N. RhoGTPases at the synapse: an embarrassment of choice.Small GTPases. 2017; 8: 106-113Crossref PubMed Scopus (3) Google Scholar]. GTPases are, in part, regulated by GEFs that facilitate the exchange of GDP for GTP, opposing the action of GTPase-activating proteins (GAPs) [7.Rossman K.L. et al.GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.Nat. Rev. Mol. Cell Biol. 2005; 6: 167-180Crossref PubMed Scopus (1125) Google Scholar]. RhoGEFs were discovered in the context of diffuse B cell lymphoma (Dbl) [8.Eva A. Aaronson S.A. Isolation of a new human oncogene from a diffuse B-cell lymphoma.Nature. 1985; 316: 273-275Crossref PubMed Google Scholar]. A distinct feature of the Dbl family of RhoGEFs is the presence of a Dbl homology (DH) domain, which is recurrently followed by a regulatory C-terminal pleckstrin homology (PH) domain, together comprising the enzymatic GEF domain [9.Cook D.R. et al.Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease.Oncogene. 2014; 33: 4021-4035Crossref PubMed Scopus (174) Google Scholar]. GEF domains are conserved across Dbl family members; however, the non-GEF sequences flanking the DH–PH domains are more divergent and act as additional regulators of intrinsic GEF function, both structurally and through facilitating protein–protein and protein–lipid interactions. This sequence diversity is a critical means by which various Dbl RhoGEF proteins display unique functions, through different subcellular targeting and sequestration, resulting in differing spatial–temporal activation of GTPases. The paralog (see Glossary) Dbl RhoGEFs Kalirin and Trio, the only RhoGEFs with tandem GEF domains, have been broadly investigated and have emerged as significant regulators of synaptic development, plasticity, and neurotransmission. Recent work has reinforced and expanded on these roles and has further positioned Kalirin and Trio as critical molecules in neurodevelopmental and neurodegenerative disorders. This review covers the recent advancements in understanding the relationship between Kalirin and Trio and highlights the current developments in their functions in synaptic physiology and, importantly, in disease. Kalirin and Trio are distinctive in that they are paralogous proteins evolving from a mutual ancestral gene via duplication. Orthologs are observed in Drosophila (dTrio) and in Caenorhabditis elegans (unc-73) (Figure 1). Kalirin and Trio are similarly divergent to both dTrio and to unc-73 [10.Schmidt S. Debant A. Function and regulation of the Rho guanine nucleotide exchange factor Trio.Small GTPases. 2014; 5e29769Crossref PubMed Scopus (10) Google Scholar]. Recent domain and phylogenetic analyses have shown that the duplication event occurred in Urbilateria, with the last common ancestor existing in Prebilateria [11.Kratzer M.C. et al.Evolution of the Rho guanine nucleotide exchange factors Kalirin and Trio and their gene expression in Xenopus development.Gene Expr. Patterns. 2019; 32: 18-27Crossref PubMed Scopus (3) Google Scholar]. The predicted core domain structure of the Kalirin/Trio-related protein in Prebilateria is thought to contain two spectrin repeats and dual GEF domains. The working model posits the single Trio/Kalrn ancestor acquired a kinase domain, resulting in the ancestral Kalrn, which was subsequently duplicated in Urbilateria to yield distinct Kalrn and Trio genes. The phylogenetic analysis found retention and loss events were unpredictable in invertebrates, with only a few invertebrate taxa having retained both proteins [11.Kratzer M.C. et al.Evolution of the Rho guanine nucleotide exchange factors Kalirin and Trio and their gene expression in Xenopus development.Gene Expr. Patterns. 2019; 32: 18-27Crossref PubMed Scopus (3) Google Scholar]. In vertebrates, Kalirin and Trio were found to contain multiple protein variants when the duplicate was present, suggesting an adaptability for novel protein function [11.Kratzer M.C. et al.Evolution of the Rho guanine nucleotide exchange factors Kalirin and Trio and their gene expression in Xenopus development.Gene Expr. Patterns. 2019; 32: 18-27Crossref PubMed Scopus (3) Google Scholar,12.Kruse K. et al.N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability.J. Cell Biol. 2019; 218: 299-316Crossref PubMed Scopus (4) Google Scholar]. This is consistent with understandings of gene duplication retention, in which gene copies are retained when they serve complementary functions (so-called subfunctionalization) [13.Ward R. Durrett R. Subfunctionalization: how often does it occur? How long does it take?.Theor. Popul. Biol. 2004; 66: 93-100Crossref PubMed Scopus (21) Google Scholar]. Indeed, many Kalirin and Trio isoforms have been identified and the proteomic diversity of Kalirin and Trio mediates their specific functions, both in developmental and tissue-specific manners (Figure 1, Box 1). For instance, C-terminal variations in Kalirin affect its trafficking and regulate its function at excitatory synapses via the inclusion of a postsynaptic density-95/discs large/zona occludens (PDZ) ligand, which is not present in any Trio isoform [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar,15.Penzes P. et al.Distinct roles for the two Rho GDP/GTP exchange factor domains of kalirin in regulation of neurite growth and neuronal morphology.J. Neurosci. 2001; 21: 8426-8434Crossref PubMed Google Scholar]. The emergence of a variety of Kalirin and Trio isoforms may indicate a degree of functional separation, which may account for the evolutionary retention of complementary Kalirin and Trio isoforms that mediated functions once served by the ancestral Kalirin/Trio.Box 1Multiple Promoters and Alternative Splicing: Trio and Kalirin Proteomic ComplexityThe Kalrn and Trio genes each give rise to numerous isoforms, due to pronounced alternative splicing and promoter usage (see Figure 1 in main text) [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar,20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar,21.Portales-Casamar E. et al.Identification of novel neuronal isoforms of the Rho-GEF Trio.Biol. Cell. 2006; 98: 183-193Crossref PubMed Scopus (0) Google Scholar,114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. Both proteins, in their full-length form, are defined by two GEF domains (GEF1 and GEF2) and a C-terminal serine/threonine kinase domain, a unique feature of these Dbl family members. Kalirin and Trio each have an N-terminal Sec14p domain trailed by numerous repeating spectrin-like repeats, with two SH3 domains following the GEF sequences, and a single immunoglobulin-like domain. Kalirin is defined further by the addition of a fibronectin-like (FN3) domain leading the C-terminal kinase domain (see Figure 1 in main text).C-terminal sequence variations are the most common variants among brain-specific Trio isoforms. Alternative splicing of Trio exon 48 results in two distinct Trio isoforms, Trio-9S and Trio-9L, which are considered the dominant brain-specific species [20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar,21.Portales-Casamar E. et al.Identification of novel neuronal isoforms of the Rho-GEF Trio.Biol. Cell. 2006; 98: 183-193Crossref PubMed Scopus (0) Google Scholar]. Trio-9S and Trio-9L most resemble full-length UNC-73 and dTrio in that they do not contain the C-terminal kinase domain. Moreover, a cerebellum-specific isoform is also observed after postnatal day 30 (in mice), termed Trio-8, which is specific to Purkinje neurons [20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar]. Trio-8 is unique in that it contains only the first Rac1/RhoG GEF domain.Like Trio, Kalirin is expressed ubiquitously and can be found in cardiac and skeletal muscle, as well as in the liver and in endocrine tissue [115.Miller M.B. et al.Neuronal Rho GEFs in synaptic physiology and behavior.Neuroscientist. 2013; 19: 255-273Crossref PubMed Scopus (40) Google Scholar]. Alterative 3′ splicing gives rise to the major Kalirin isoforms, Kalirin-12, Kalirin-9, and Kalirin-7. Kalirin-12 retains both GEF1 and GEF2 domains, as well as the kinase domain. Kalirin-9, however, lacks the kinase domain and is most similar to Trio-9 [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar]. Kalirin-7 is the brain specific isoform of Kalirin, as well as the dominant species in the adult [116.Penzes P. et al.An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction.J. Biol. Chem. 2000; 275: 6395-6403Crossref PubMed Scopus (106) Google Scholar]. Kalirin-7 is most similar to Trio-8 in that it contains only the Rac1/RhoG GEF. It is, however, unique in that it contains a putative PDZ [postsynaptic density protein, Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein] interacting motif at its C-terminal end (see Figure 1 in main text) [116.Penzes P. et al.An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction.J. Biol. Chem. 2000; 275: 6395-6403Crossref PubMed Scopus (106) Google Scholar]. Moreover, recent work has identified additional alternative promotor usage that gives rise to further Kalirin-7 species with differing N-terminal sequences; with bKalirin-7 and cKalirin-7 being most prevalent, differing in only 25 amino acids (see Figure 1 in main text) [114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. These N-terminal differences are thought to mediate unique phosphoinositide-dependent interactions that control Kalirin-7 protein localization and function [114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. An additional Kalirin-7 variant, termed ΔKalirin-7 or -5, lacks the N-terminal Sec14 domain and first four spectrin repeats, but retains the PDZ-interacting motif [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar]. The Kalrn and Trio genes each give rise to numerous isoforms, due to pronounced alternative splicing and promoter usage (see Figure 1 in main text) [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar,20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar,21.Portales-Casamar E. et al.Identification of novel neuronal isoforms of the Rho-GEF Trio.Biol. Cell. 2006; 98: 183-193Crossref PubMed Scopus (0) Google Scholar,114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. Both proteins, in their full-length form, are defined by two GEF domains (GEF1 and GEF2) and a C-terminal serine/threonine kinase domain, a unique feature of these Dbl family members. Kalirin and Trio each have an N-terminal Sec14p domain trailed by numerous repeating spectrin-like repeats, with two SH3 domains following the GEF sequences, and a single immunoglobulin-like domain. Kalirin is defined further by the addition of a fibronectin-like (FN3) domain leading the C-terminal kinase domain (see Figure 1 in main text). C-terminal sequence variations are the most common variants among brain-specific Trio isoforms. Alternative splicing of Trio exon 48 results in two distinct Trio isoforms, Trio-9S and Trio-9L, which are considered the dominant brain-specific species [20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar,21.Portales-Casamar E. et al.Identification of novel neuronal isoforms of the Rho-GEF Trio.Biol. Cell. 2006; 98: 183-193Crossref PubMed Scopus (0) Google Scholar]. Trio-9S and Trio-9L most resemble full-length UNC-73 and dTrio in that they do not contain the C-terminal kinase domain. Moreover, a cerebellum-specific isoform is also observed after postnatal day 30 (in mice), termed Trio-8, which is specific to Purkinje neurons [20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar]. Trio-8 is unique in that it contains only the first Rac1/RhoG GEF domain. Like Trio, Kalirin is expressed ubiquitously and can be found in cardiac and skeletal muscle, as well as in the liver and in endocrine tissue [115.Miller M.B. et al.Neuronal Rho GEFs in synaptic physiology and behavior.Neuroscientist. 2013; 19: 255-273Crossref PubMed Scopus (40) Google Scholar]. Alterative 3′ splicing gives rise to the major Kalirin isoforms, Kalirin-12, Kalirin-9, and Kalirin-7. Kalirin-12 retains both GEF1 and GEF2 domains, as well as the kinase domain. Kalirin-9, however, lacks the kinase domain and is most similar to Trio-9 [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar]. Kalirin-7 is the brain specific isoform of Kalirin, as well as the dominant species in the adult [116.Penzes P. et al.An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction.J. Biol. Chem. 2000; 275: 6395-6403Crossref PubMed Scopus (106) Google Scholar]. Kalirin-7 is most similar to Trio-8 in that it contains only the Rac1/RhoG GEF. It is, however, unique in that it contains a putative PDZ [postsynaptic density protein, Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein] interacting motif at its C-terminal end (see Figure 1 in main text) [116.Penzes P. et al.An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction.J. Biol. Chem. 2000; 275: 6395-6403Crossref PubMed Scopus (106) Google Scholar]. Moreover, recent work has identified additional alternative promotor usage that gives rise to further Kalirin-7 species with differing N-terminal sequences; with bKalirin-7 and cKalirin-7 being most prevalent, differing in only 25 amino acids (see Figure 1 in main text) [114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. These N-terminal differences are thought to mediate unique phosphoinositide-dependent interactions that control Kalirin-7 protein localization and function [114.Miller M.B. et al.Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin-7.J. Neurochem. 2017; 140: 889-902Crossref PubMed Scopus (5) Google Scholar]. An additional Kalirin-7 variant, termed ΔKalirin-7 or -5, lacks the N-terminal Sec14 domain and first four spectrin repeats, but retains the PDZ-interacting motif [14.Johnson R.C. et al.Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J. Biol. Chem. 2000; 275: 19324-19333Crossref PubMed Scopus (70) Google Scholar]. Kalirin and Trio are both present throughout development and into adulthood, with differing isoform-specific expressions and subcellular localizations. A distinct expression difference is that Trio, but not Kalrn, is expressed in migrating neural crest cells in Xenopus laevis, suggesting Trio isoforms may be more important in organization of neural tissue relative to Kalirin [11.Kratzer M.C. et al.Evolution of the Rho guanine nucleotide exchange factors Kalirin and Trio and their gene expression in Xenopus development.Gene Expr. Patterns. 2019; 32: 18-27Crossref PubMed Scopus (3) Google Scholar,16.Ma X.M. et al.Kalirin-7 is required for synaptic structure and function.J. Neurosci. 2008; 28: 12368-12382Crossref PubMed Scopus (114) Google Scholar]. This is consistent with their respective knockout phenotypes in mice [17.O'Brien S.P. et al.Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 12074-12078Crossref PubMed Scopus (116) Google Scholar]. In the central nervous system (CNS) of vertebrates, larger Kalirin isoforms are expressed abundantly early in development and localize to growth cones, whereas the brain-specific isoform Kalirin-7 localizes to the postsynaptic density (PSD), with expression paralleling that of synaptogenesis [18.Penzes P. Jones K.A. Dendritic spine dynamics – a key role for kalirin-7.Trends Neurosci. 2008; 31: 419-427Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Kalirin-7 is expressed abundantly in the adult cortex and hippocampus, and persists as the dominant brain-specific isoform in the adult. However, there is an age-dependent increase in larger Kalirin isoform expression in orbitofrontal cortex [19.Grubisha M.J. et al.Age-dependent increase in Kalirin-9 and Kalirin-12 transcripts in human orbitofrontal cortex.Eur. J. Neurosci. 2016; 44: 2483-2492Crossref PubMed Scopus (2) Google Scholar]. Trio, likewise, displays dynamic expression patterns in embryonic and adult tissues, though the available isoform-specific data are less specific. Trio expression is apparent by embryonic day 10 in the neocortex and cerebellum, with the exception of Trio-8, which is limited to the cerebellar Purkinje neurons at P30 onward [20.McPherson C.E. et al.Multiple novel isoforms of Trio are expressed in the developing rat brain.Gene. 2005; 347: 125-135Crossref PubMed Scopus (36) Google Scholar,21.Portales-Casamar E. et al.Identification of novel neuronal isoforms of the Rho-GEF Trio.Biol. Cell. 2006; 98: 183-193Crossref PubMed Scopus (0) Google Scholar]. While Trio is known to localize to growth cones, the presynaptic terminal, and the PSD, the exact temporal and isoform-specific expression patterns are not clearly delineated. Actin cytoskeleton regulation by Rho GTPases is central for cell migration and polarization, with Trio and Kalirin participating as key players in these processes. In particular, studies have established the importance of Trio in neurite growth and axon guidance. Trio has been shown to function in neurite formation downstream of the neurotrophin nerve growth factor (NGF) via RhoG activation in PC12 cells [22.Estrach S. et al.The Human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth.Curr. Biol. 2002; 12: 307-312Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. These data are challenging to interpret, as extensions in PC12 cells are not neurites precisely. However, the NGF downstream target Kidins220 has been shown to interact with Trio and activate it, resulting in Rac1 activation and neurite extension both in PC12 cells and in hippocampal neurons, supporting the role of NGF in Trio-mediated neurite extension [23.Neubrand V.E. et al.Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio.J. Cell Sci. 2010; 123: 2111-2123Crossref PubMed Scopus (40) Google Scholar]. dTrio is also known to interact with the Netrin receptor Frazzled as part of a signaling network regulating CNS midline axon guidance in Drosophila [24.Forsthoefel D.J. et al.The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila.Development. 2005; 132: 1983-1994Crossref PubMed Scopus (89) Google Scholar]. Indeed, Netrin-1-mediated Rac1 activation in the mouse is dependent on Trio for normal axon guidance, as revealed by the reduction in Netrin-1-induced Rac1 activation and axon guidance in the absence of Trio [25.Briancon-Marjollet A. et al.Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance.Mol. Cell. Biol. 2008; 28: 2314-2323Crossref PubMed Scopus (0) Google Scholar,26.Peng Y.J. et al.Trio is a key guanine nucleotide exchange factor coordinating regulation of the migration and morphogenesis of granule cells in the developing cerebellum.J. Biol. Chem. 2010; 285: 24834-24844Crossref PubMed Scopus (49) Google Scholar]. This mechanism also involves the interaction with heat shock cognate protein 70 (Hsc70) and the phosphorylation of Trio at Y2622 by the Src kinase Fyn [27.DeGeer J. et al.Tyrosine phosphorylation of the Rho guanine nucleotide exchange factor Trio regulates netrin-1/DCC-mediated cortical axon outgrowth.Mol. Cell. Biol. 2013; 33: 739-751Crossref PubMed Scopus (34) Google Scholar,28.DeGeer J. et al.Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1.J. Cell Biol. 2015; 210: 817-832Crossref PubMed Scopus (13) Google Scholar]. The bulk of developmental studies on Trio have focused on Rac1/RhoG regulation; indeed, the GEF1 domain of Trio is sufficient for neurite outgrowth [29.Bellanger J.M. et al.Different regulation of the Trio Dbl-Homology domains by their associated PH domains.Biol. Cell. 2003; 95: 625-634Crossref PubMed Scopus (0) Google Scholar]. Several studies have shown that the GEF2 domain of Trio is natively inhibited, and its activation results in restriction of neurite extension and dendritic branching [29.Bellanger J.M. et al.Different regulation of the Trio Dbl-Homology domains by their associated PH domains.Biol. Cell. 2003; 95: 625-634Crossref PubMed Scopus (0) Google Scholar, 30.Bandekar S.J. et al.Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.Sci. Signal. 2019; (Published online February 19, 2019. https://doi.org/10.1126/scisignal.aav2449)Crossref PubMed Scopus (1) Google Scholar, 31.Iyer S.C. et al.The RhoGEF trio functions in sculpting class specific dendrite morphogenesis in Drosophila sensory neurons.PLoS One. 2012; 7e33634Crossref PubMed Scopus (31) Google Scholar, 32.Awasaki T. et al.The Drosophila trio plays an essential role in patterning of axons by regulating their directional extension.Neuron. 2000; 26: 119-131Abstract Full Text Full Text PDF PubMed Google Scholar]. In this regard, the dual GEF domains of Trio provide dynamic regulation of neurite outgrowth and dendritic branching, with GEF1 mediating neurite extension and GEF2 destabilizing this process via RhoA activation. Recent studies of activation of RhoA by Trio have suggested it is additionally involved in axon guidance. Slit homolog protein 2 (Slit2), a secreted glycoprotein involved in axon guidance and neuronal migration, induces RhoA activation through Trio, which is important for telencephalic wiring [33.Backer S. et al.Trio GEF mediates RhoA activation downstream of Slit2 and coordinates telencephalic wiring.Development. 2018; 145Crossref PubMed Scopus (0) Google Scholar]. Slit2 is a ligand for the Roundabout (Robo/SAX-3) receptors, which are regulated by unc-73, possibly linking Slit2's regulation of Trio RhoA GTPases via this receptor [34.Watari-Goshima N. et al.C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations.Nat. Neurosci. 2007; 10: 169-176Crossref PubMed Scopus (0) Google Scholar]. It is evident that both Trio GEF domains are necessary for regulated neurite outgrowth and guidance; however, the role of additional Trio domains in this process has remained largely unknown. It has been demonstrated that Golgi-resident Trio regulates membrane trafficking in developing cerebellar granule cells via interactions of its N-terminal spectrin repeats with RABIN8, resulting in RAB8 and RAB10 activation [35.Tao T. et al.Golgi-resident TRIO regulates membrane trafficking during neurite outgrowth.J. Biol. Chem. 2019; 294: 10954-10968Crossref PubMed Scopus (2) Google Scholar]. Expression of active RAB8 and RAB10 is able to restore neuri
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