{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T23:55:44Z","timestamp":1787702144605,"version":"build-2784847793"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T00:00:00Z","timestamp":1712016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST)"},{"name":"Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)"},{"name":"Japanese Ministry of Health, Labour and Welfare (MHLW)"},{"name":"Daiichi Sankyo Science Foundation"},{"name":"Japan Foundation for Pediatric Research"},{"name":"Mishima Kaiun Memorial Foundation"},{"name":"Mitsubishi Tanabe Science Foundation"},{"name":"Otsuka Science Foundation"},{"name":"Takeda Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger\u2019s syndrome, and pervasive developmental disorder. Individuals with ASD may exhibit difficulties in social interactions, communication challenges, repetitive behaviors, and restricted interests. While genetic mutations in individuals with ASD can either activate or inactivate the activities of the gene product, impacting neuronal morphogenesis and causing symptoms, the underlying mechanism remains to be fully established. Herein, for the first time, we report that genetically conserved Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules control process elongation in the N1E-115 cell line, a model line capable of achieving neuronal morphological changes. The increased elongation phenotypes observed in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) Arg676-to-Cys [p.R676C] were also mediated by Dock5 signalosome molecules. Indeed, knockdown of Dock5 using clustered regularly interspaced short palindromic repeat (CRISPR)\/CasRx-based guide(g)RNA specifically recovered the mutated Sema5A-induced increase in process elongation in cells. Knockdown of Elmo2, an adaptor molecule of Dock5, also exhibited similar recovery. Comparable results were obtained when transfecting the interaction region of Dock5 with Elmo2. The activation of c-Jun N-terminal kinase (JNK), one of the primary signal transduction molecules underlying process elongation, was ameliorated by either their knockdown or transfection. These results suggest that the Dock5 signalosome comprises abnormal signaling involved in the process elongation induced by ASD- and ID-associated Sema5A. These molecules could be added to the list of potential therapeutic target molecules for abnormal neuronal morphogenesis in ASD at the molecular and cellular levels.<\/jats:p>","DOI":"10.3390\/cimb46040194","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T03:37:21Z","timestamp":1712115441000},"page":"3092-3107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Autism Spectrum Disorder- and\/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape"],"prefix":"10.3390","volume":"46","author":[{"given":"Miyu","family":"Okabe","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanari","family":"Sato","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikito","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asahi","family":"Honjo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Okawa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Ishida","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-1611","authenticated-orcid":false,"given":"Mutsuko","family":"Kukimoto-Niino","sequence":"additional","affiliation":[{"name":"Laboratory for Protein Functional and Structural Biology, Center for Biosystems Dynamics Research, RIKEN, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Shirouzu","sequence":"additional","affiliation":[{"name":"Laboratory for Protein Functional and Structural Biology, Center for Biosystems Dynamics Research, RIKEN, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9298-5799","authenticated-orcid":false,"given":"Yuki","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"},{"name":"Laboratory of Molecular Pharmacology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3618-998X","authenticated-orcid":false,"given":"Junji","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"},{"name":"Laboratory for Protein Functional and Structural Biology, Center for Biosystems Dynamics Research, RIKEN, Yokohama 230-0045, Japan"},{"name":"Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev.ne.17.030194.001411","article-title":"Neuronal polarity","volume":"17","author":"Craig","year":"1994","journal-title":"Annu. 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