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Although DCHS1\u2013FAT4 binding is mediated by their respective extracellular domains, the in vivo function of the DCHS1 intracellular domain (ICD) is poorly defined. To test its function, we generated mice in which the DCHS1 ICD was deleted and replaced with a V5 epitope tag (Dchs1\u0394ICD-V5). Homozygous Dchs1\u0394ICD-V5\/\u0394ICD-V5 mice are viable but exhibit VMS-like craniofacial flattening with enlarged fontanelles and reduced palatine\/maxillary structures, along with airway cartilage abnormalities including reduced mineralization and decreased tracheal circularity. In periventricular regions, wild-type DCHS1 expression shows polarized localization, whereas mice with the ICD deletion exhibit altered cell polarization within the subventricular zone, concomitant with changes in neural cellular distribution. Neonatal brains display reduced pYAP1: YAP1 ratios and increased Ki67+ proliferation with greater Ki67\u2013neuronal co-localization within the periventricular zone. Together, these data identify the DCHS1 ICD as a critical effector for DCHS1 signaling and a regulator of polarity-dependent growth, with associated changes in Hippo pathway activity during craniofacial and neural morphogenesis. Additionally, our data establish Dchs1\u0394ICD-V5\/\u0394ICD-V5 mice as a model that recapitulates core features of VMS, thereby allowing new mechanistic discoveries into its pathogenesis.<\/jats:p>","DOI":"10.3390\/cells15070587","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:48:41Z","timestamp":1774532921000},"page":"587","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of the DCHS1 Intracellular Domain Expands Neurogenic Proliferation and Generates Van Maldergem-like Neurodevelopmental Defects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9894-4496","authenticated-orcid":false,"given":"Kathryn","family":"Byerly","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cayla","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3045-4025","authenticated-orcid":false,"given":"Magdalena","family":"Brei","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Parris","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Alston","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8374-8513","authenticated-orcid":false,"given":"Hanmei","family":"Dong","sequence":"additional","affiliation":[{"name":"Clemson-MUSC Bioengineering Program, Department of Bioengineering, Clemson University, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-4671","authenticated-orcid":false,"given":"Peng","family":"Chen","sequence":"additional","affiliation":[{"name":"Clemson-MUSC Bioengineering Program, Department of Bioengineering, Clemson University, Charleston, SC 29425, USA"},{"name":"Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5130-5128","authenticated-orcid":false,"given":"Hai","family":"Yao","sequence":"additional","affiliation":[{"name":"Clemson-MUSC Bioengineering Program, Department of Bioengineering, Clemson University, Charleston, SC 29425, USA"},{"name":"Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2102-1137","authenticated-orcid":false,"given":"Fulei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Guz","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-0148","authenticated-orcid":false,"given":"Sarah","family":"Dooley","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1524-5804","authenticated-orcid":false,"given":"Taylor","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5912-0329","authenticated-orcid":false,"given":"Brian","family":"Loizzi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0625-2449","authenticated-orcid":false,"given":"Ranan","family":"Phookan","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 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