{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:18:23Z","timestamp":1787807903208,"version":"build-2784847793"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00097mb19","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Japanese Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Japanese Ministry of Health, Labour and Welfare","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03mwa7s65","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02y123g31","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Neuroligin-2 (NLGN2) is a cell adhesion molecule implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID). While NLGN2 is well known as a postsynaptic organizer of predominantly inhibitory synapses, accumulating evidence suggests that NLGN family proteins are also involved in neuronal morphogenesis during early developmental stages. However, a gap remains in our understanding of how loss of function in NLGN2 potentially leads to abnormal neuronal morphogenesis. Here, we investigated the molecular basis of excessive neuronal process formation induced by depletion of NLGN2 using the N1E-115 cell line, an established model of neuronal differentiation. Clustered regularly interspaced short palindromic repeat (CRISPR)\/Cas13-mediated knockdown of NLGN2 promoted neuronal process elongation and neuronal differentiation marker expression. Mechanistically, NLGN2 knockdown resulted in activation of coiled-coil and hook domain-containing protein 88A (CCDC88A, also known as Girdin or GIV), a non-receptor guanine nucleotide exchange factor for heterotrimeric G proteins. Transfection of the regulator of G protein signaling (RGS) domain of RGS3, a negative regulator of G proteins, or the G protein-binding domain of engulfment and cell motility 1 (ELMO1) effectively decreased the excessive process elongation phenotype. Similar effects were observed in primary cortical neurons. Furthermore, these interventions normalized elevated Rac1 activity induced by NLGN2 knockdown. Collectively, our findings identify the CCDC88A-G protein-ELMO signaling pathway as a key mediator of excessive neuronal morphogenesis following NLGN2 knockdown. These results provide valuable insight into the mechanisms by which NLGN2 dysfunction may contribute to abnormal neuronal morphogenesis and suggest potential recovery strategies.<\/jats:p>","DOI":"10.3390\/ijms27177612","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:57:17Z","timestamp":1787662637000},"page":"7612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling NDD-Associated NLGN2 Depletion Using CRISPR\/Cas13 Reveals Exaggerated Process Elongation Mediated by the CCDC88A-G Protein\u2013ELMO Axis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-8488","authenticated-orcid":false,"given":"Hideji","family":"Yako","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikito","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Tada","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitona","family":"Waragai","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, 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 Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"},{"name":"Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, 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 Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan"},{"name":"Department of Biological Sciences, Tokyo College of Biotechnology, Ota, Tokyo 157-8535, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S2215-0366(16)30376-5","article-title":"Neurodevelopmental disorders","volume":"4","author":"Thapar","year":"2017","journal-title":"Lancet Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1097\/WCO.0000000000000710","article-title":"What are neurodevelopmental disorders?","volume":"32","author":"Ismail","year":"2019","journal-title":"Curr. 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