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A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein\u2013family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1\u2013mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    DCC ortholog, was required for attractive signaling in vivo at the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    . The findings reveal the WRC as a pivotal component of netrin-1\u2013DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adk2345","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T13:58:52Z","timestamp":1727791132000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1\u2013DCC"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3533-3027","authenticated-orcid":true,"given":"Karina","family":"Chaudhari","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3515-3632","authenticated-orcid":true,"given":"Kaiyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."},{"name":"Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2B4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-3151","authenticated-orcid":true,"given":"Patricia T.","family":"Yam","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0900-8052","authenticated-orcid":true,"given":"Yixin","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7159-9562","authenticated-orcid":true,"given":"Daniel A.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-0737","authenticated-orcid":true,"given":"Sabrina","family":"Schlienger","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."},{"name":"Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1859-3995","authenticated-orcid":true,"given":"Sara","family":"Calabretta","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2155-7209","authenticated-orcid":true,"given":"Jean-Francois","family":"Michaud","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9954-2357","authenticated-orcid":true,"given":"Meagan","family":"Collins","sequence":"additional","affiliation":[{"name":"McGill University Health Center Research Institute, Montreal, QC H4A 3J1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9607-8229","authenticated-orcid":true,"given":"Junmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-0508","authenticated-orcid":true,"given":"Myriam","family":"Srour","sequence":"additional","affiliation":[{"name":"McGill University Health Center Research Institute, Montreal, QC H4A 3J1, Canada."},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada."},{"name":"Department of Pediatrics, Division of Pediatric Neurology, McGill University, Montreal, QC H4A 3J1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-159X","authenticated-orcid":true,"given":"Baoyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-8672","authenticated-orcid":true,"given":"Fr\u00e9d\u00e9ric","family":"Charron","sequence":"additional","affiliation":[{"name":"Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada."},{"name":"Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2B4, Canada."},{"name":"Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada."},{"name":"Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg J.","family":"Bashaw","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, 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