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Rho Gtpase Regulators and Effectors in Autism Spectrum Disorders

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Rho Gtpase Regulators and Effectors in Autism Spectrum Disorders cells Review Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics Daji Guo , Xiaoman Yang and Lei Shi * JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; [email protected] (D.G.); [email protected] (X.Y.) * Correspondence: [email protected] or [email protected]; Tel.: +86-020-85222120 Received: 26 February 2020; Accepted: 26 March 2020; Published: 31 March 2020 Abstract: The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed. Keywords: Rho GTPase; autism spectrum disorder; guanine nuclear exchange factor; GTPase-activating protein; animal model; behavior 1. Introduction Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two core symptoms: (1) impaired social interaction and communication, and (2) repetitive or restricted interest and behaviors. The average global prevalence of ASD is ~0.62% [1], and studies in Europe and Asia have identified individuals with ASD with an average prevalence between 1% and 2% [2–6]. Statistics from CDC (Centers for Disease Control and Prevention)’s Autism and Developmental Disabilities Monitoring (ADDM) Network revealed that one in 59 children were diagnosed with ASD in United States in 2018 [7]. In addition, there is a high rate of co-occurring mental health disorders in ASD patients [8]. Meta-analysis of twin studies show that monozygotic twins have significantly higher concordance rate of ASD than dizygotic twins [9,10], thus the aetiology of ASD is closely related to genetic component. However, the genetic causes of ASD are very complex as a huge number of genes contribute to the pathogenesis of ASD. Therefore, databases of ASD-related genes, such as SFARI (Simons foundation autism research initiative) Gene [11,12] and AutDB (the autism gene database) [13], have been established. With the development of genome sequencing, increasing genes related to ASD have been identified. As of November 2019, more than 800 genes have been included in SFARI Gene [14] and more than 1000 genes have been listed in AutDB [15]. Among these ASD susceptibility genes, many converge on synapse regulation such as the regulation of development and maturation of synaptic contacts and synaptic transmission [16–18]. Cells 2020, 9, 835; doi:10.3390/cells9040835 www.mdpi.com/journal/cells Cells 2020, 9, 835 2 of 38 Cells 2020, 9, x FOR PEER REVIEW 2 of 37 In the nervous nervous system, system, precise precise neuronal neuronal connectivit connectivityy depends depends on onsynapses. synapses. It is Itwell is well known known that thatdendritic dendritic spines, spines, which which are enriched are enriched with with filament filamentousous actin, actin, are aredynamic dynamic structures structures important important for forsynapse synapse formation, formation, function function and andplasticity plasticity [19]. [19Rho]. family Rho family GTPases GTPases are key are regulators key regulators of the of actin the actincytoskeleton cytoskeleton that play that critical play critical roles in roles axonal in axonaloutgrowth, outgrowth, dendritic dendritic spine morphogenesis, spine morphogenesis, and synapse and synapseformation formation [20]. The [Rho20]. Thefamily Rho GTPases, family GTPases, which belo whichng to belong the Ras to superfamily, the Ras superfamily, are small are G proteins small G proteinssized ~20 sized KDa. ~20 Human KDa. HumanRho family Rho GTPases family GTPases include include20 members 20 members that can that be canclassified be classified into eight into eightgroups groups [21,22]. [21 By,22 ].cycling By cycling between between GTP-bound GTP-bound active active forms forms and GDP-bound and GDP-bound inactive inactive forms, forms, Rho RhoGTPases GTPases regulate regulate a diverse a diverse array array of ofcellular cellular events, events, including including the the control control of of growth, growth, migration, adhesion, and didifferentiation.fferentiation. Rho GTPase activity is regulated by two different different kinds of regulatory protein: guanine nucleotide exchange factors (GEFs) (GEFs),, which catalyze catalyze the the replacement replacement of of GDP GDP by by GTP, GTP, enabling the GTPases to recognize downstream effe effectors,ctors, and GTP-activating proteins (GAPs), which negatively regulate GTPase activity by favoring the GDP-boundGDP-bound forms [[19,23].19,23]. Rho GTPase activity regulation is a complex process as 82 GEFs [[24,25]24,25] and 66 GAPsGAPs (of whichwhich 5757 havehave aa commoncommon GAPGAP domain) [[26]26] have been identifiedidentified so farfar inin humans.humans. The complexity of Rho GTPase signaling is also contributed by their downstream eeffectors,ffectors, as there are over 70 downstream eeffectorsffectors identifiedidentified to be capable of transducing signalssignals from RhoRho GTPasesGTPases [[27].27]. A number of extensive review articles have summarizedsummarized the impact of Rho family GTPases in neural development and diseases [[23,28–33].23,28–33]. Moreover, multiple lines of evidence have suggestedsuggested that RhoRho GTPaseGTPase signalingsignaling maymay contributecontribute to to the the pathogenesis pathogenesis of of ASD. ASD. By By searching searching SFARI SFARI Gene, Gene, it isit notableis notable to findto find that that 8.53% 8.53% (seven (seven in 82) in of82) RhoGEFs, of RhoGEFs, 12.28% 12.28% (seven (seven in 57) in of 57) RhoGAPs of RhoGAPs and 8.21% and (six8.21% in 73)(sixRho in 73) eff Rhoectors effectors are categorized are categorized as ASD-risk as ASD-risk genes (Figure genes 1(Figure); 2.40% 1); (20 2.40% in 831) (20 ASD-risk in 831) ASD-risk genes directly genes participatedirectly participate in Rho GTPase in Rho signaling.GTPase signaling. We also find We thatalso allfind these that genes all these encode genes regulatory encode proteinsregulatory or eproteinsffectors ofor threeeffectors most-well of three studied most-well Rho studied GTPases, Rho Ras GTPases, homolog Ras family homolog member family A (RhoA), member cell A division(RhoA), cyclecell division 42 (Cdc42), cycle and42 (Cdc42), Ras-related and C3Ras-related Botulinum C3 Toxin Botulinum Substrate Toxin 1 (Rac1)Substrate (Table 1 (Rac1)1). In this(Table review, 1). In thethis clinicalreview, evidence the clinical and evidence animal modelsand animal of these models 20 genes of these are 20 summarized. genes are summarized. Moreover, therapeutic Moreover, approachestherapeutic approaches that are capable that are of correctingcapable of thecorrecti abnormalitiesng the abnormalities caused by dysfunctionscaused by dysfunctions of these Rho of GTPasethese Rho regulators GTPase regulators and effectors and are effectors discussed. are discussed. Figure 1. Overlap of human gene sets of RhoGEFs, RhoGAPs, and Rho effectors with autism spectrum Figure 1. Overlap of human gene sets of RhoGEFs, RhoGAPs, and Rho effectors with autism spectrum disorder (ASD) risk genes inin SimonsSimons foundationfoundation autismautism researchresearch initiativeinitiative (SFARI).(SFARI). Table 1. Rho family GTPases involved in ASD. 2 Cells 2020, 9, 835 3 of 38 Table 1. Rho family GTPases involved in ASD. Upstream/DOWNSTREAM Rho ASD Candidate Gene Gene Name Chromosome Location Genetic Category SFARI Gene Score GTPase(s) Rho GTPase GEF Cdc42 guanine nucleotide exchange factor Rare Single Gene Category 1 (High ARHGEF9 Xq11.1-q11.2 CDC42 (GEF) 9 Mutation, Syndromic Confidence) Rare Single Gene Category 1 (High TRIO Trio Rho guanine nucleotide exchange factor 5p15.2 RHOA, RAC1 Mutation, Syndromic Confidence) Rare Single Gene Category 2 (Strong DOCK8 Dedicator of cytokinesis 8 9p24.3 CDC42 Mutation Candidate) Phosphatidylinositol-3,4,5-trisphosphate-dependent Category 2 (Strong PREX1 20q13.13 Genetic Association RAC1 Rac exchange factor 1 Candidate) Rare Single Gene Category 3 (Suggestive ARHGEF10 Rho guanine nucleotide exchange factor 10 8p23.3 RHOA Mutation, Functional Evidence) Rare Single Gene Category 3 (Suggestive DOCK1 Dedicator of cytokinesis 1 10q26.2 RAC1 Mutation Evidence) Rare Single Gene Category 3 (Suggestive DOCK4 Dedicator of cytokinesis 4 7q31.1 Mutation, Genetic RAC1 Evidence) Association, functional Rho GTPase GAP Rare Single Gene Category 2 (Strong MYO9B Myosin IXB 19p13.11 RHOA Mutation Candidate) Rare Single Gene Category 2 (Strong OPHN1 Oligophrenin 1 Xq12 RHOA, RAC1, CDC42 Mutation, Syndromic Candidate)
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