{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:21:52Z","timestamp":1790814112159,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R03HD104901"],"award-info":[{"award-number":["R03HD104901"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R21HD106580"],"award-info":[{"award-number":["R21HD106580"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3\u03b2 and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3\u03b2 at these concentrations. The knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.<\/jats:p>","DOI":"10.3390\/cells12131697","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T02:23:09Z","timestamp":1687746189000},"page":"1697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects"],"prefix":"10.3390","volume":"12","author":[{"given":"Taylor N.","family":"Takla","sequence":"first","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roksolana","family":"Sudyk","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Clayton","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2504-9455","authenticated-orcid":false,"given":"Neeta L.","family":"Vora","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan Z.","family":"Sexton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack M.","family":"Parent","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Michigan Neuroscience Institute, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1666-4106","authenticated-orcid":false,"given":"Andrew M.","family":"Tidball","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical School, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1002\/bdra.23461","article-title":"Population-based birth defects data in the United States, 2008 to 2012: Presentation of state-specific data and descriptive brief on variability of prevalence","volume":"103","author":"Mai","year":"2015","journal-title":"Birth Defects Res. 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