{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T21:05:57Z","timestamp":1773176757471,"version":"3.50.1"},"reference-count":38,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1233,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107474\/Z\/15\/Z"],"award-info":[{"award-number":["107474\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research Council","award":["J003794"],"award-info":[{"award-number":["J003794"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Human mutations in the planar cell polarity component VANGL2 are associated with the neural tube defect spina bifida. Homozygous Vangl2 mutation in mice prevents initiation of neural tube closure, precluding analysis of its subsequent roles in neurulation. Spinal neurulation involves rostral-to-caudal \u201czippering\u201d until completion of closure is imminent, when a caudal-to-rostral closure point, \u201cClosure 5\u201d, arises at the caudal-most extremity of the posterior neuropore (PNP). Here we used Grhl3Cre to delete Vangl2 in the surface ectoderm (SE) throughout neurulation and in an increasing proportion of PNP neuroepithelial cells at late neurulation stages. This deletion impaired PNP closure after the \u223c25 somite stage and resulted in caudal spina bifida in 67% of Grhl3Cre\/+Vangl2Fl\/Fl embryos. In the dorsal SE, Vangl2 deletion diminished rostrocaudal cell body orientation, but not directional polarisation of cell divisions. In the PNP, Vangl2 disruption diminished mediolateral polarisation of apical neuroepithelial F-actin profiles and resulted in eversion of the caudal PNP. This eversion prevented elevation of the caudal PNP neural folds, which in control embryos is associated with formation of Closure 5 around the 25 somite stage. Closure 5 formation in control embryos is associated with a reduction in mechanical stress withstood at the main zippering point, as inferred from the magnitude of neural fold separation following zippering point laser ablation. This stress accommodation did not happen in Vangl2-disrupted embryos. Thus, disruption of Vangl2-dependant planar polarized processes in the PNP neuroepithelium and SE preclude zippering point biomechanical accommodation associated with Closure 5 formation at the completion of PNP closure.<\/jats:p>","DOI":"10.1242\/dmm.032219","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T00:30:17Z","timestamp":1520901017000},"source":"Crossref","is-referenced-by-count":47,"title":["Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-1342","authenticated-orcid":false,"given":"Gabriel L.","family":"Galea","sequence":"first","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oleksandr","family":"Nychyk","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo A.","family":"Mole","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale","family":"Moulding","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn","family":"Savery","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evanthia","family":"Nikolopoulou","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah J.","family":"Henderson","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-5248","authenticated-orcid":false,"given":"Nicholas D. E.","family":"Greene","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-9117","authenticated-orcid":false,"given":"Andrew J.","family":"Copp","sequence":"additional","affiliation":[{"name":"Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2021042612351199900_DMM032219C1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/978-1-4939-6371-3_13","article-title":"Segmentation and quantitative analysis of epithelial tissues","volume":"1478","author":"Aigouy","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"2021042612351199900_DMM032219C2","doi-asserted-by":"publisher","first-page":"e46213","DOI":"10.1371\/journal.pone.0046213","article-title":"Molecular characterisation of endogenous Vangl2\/Vangl1 heteromeric protein complexes","volume":"7","author":"Belotti","year":"2012","journal-title":"PLoS ONE"},{"key":"2021042612351199900_DMM032219C3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.devcel.2009.11.014","article-title":"Local protease signaling contributes to neural tube closure in the mouse embryo","volume":"18","author":"Camerer","year":"2010","journal-title":"Dev. Cell"},{"key":"2021042612351199900_DMM032219C4","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.ydbio.2015.10.027","article-title":"The spatio-temporal domains of Frizzled6 action in planar polarity control of hair follicle orientation","volume":"409","author":"Chang","year":"2016","journal-title":"Dev. Biol."},{"key":"2021042612351199900_DMM032219C5","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nature04375","article-title":"Planar cell polarity signalling couples cell division and morphogenesis during neurulation","volume":"439","author":"Ciruna","year":"2006","journal-title":"Nature"},{"key":"2021042612351199900_DMM032219C6","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/S0960-9822(03)00374-9","article-title":"Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse","volume":"13","author":"Curtin","year":"2003","journal-title":"Curr. Biol."},{"key":"2021042612351199900_DMM032219C7","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1038\/ncb1784","article-title":"Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles","volume":"10","author":"Devenport","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"2021042612351199900_DMM032219C8","doi-asserted-by":"publisher","first-page":"3008","DOI":"10.1242\/dev.091173","article-title":"Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity","volume":"140","author":"Escobedo","year":"2013","journal-title":"Development"},{"key":"2021042612351199900_DMM032219C9","doi-asserted-by":"publisher","first-page":"E5177","DOI":"10.1073\/pnas.1700934114","article-title":"Biomechanical coupling facilitates spinal neural tube closure in mouse embryos","volume":"114","author":"Galea","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042612351199900_DMM032219C10","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.devcel.2016.11.003","article-title":"Basal cell-extracellular matrix adhesion regulates force transmission during tissue morphogenesis","volume":"39","author":"Goodwin","year":"2016","journal-title":"Dev. Cell"},{"key":"2021042612351199900_DMM032219C11","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1093\/hmg\/ddm221","article-title":"Increased expression of Grainyhead-like-3 rescues spina bifida in a folate-resistant mouse model","volume":"16","author":"Gustavsson","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2021042612351199900_DMM032219C12","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/bdra.23079","article-title":"A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects","volume":"94","author":"Juriloff","year":"2012","journal-title":"Birth Defects Res. A Clin. Mol. Teratol"},{"key":"2021042612351199900_DMM032219C13","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1098\/rstb.2000.0626","article-title":"Mechanisms of convergence and extension by cell intercalation","volume":"355","author":"Keller","year":"2000","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"2021042612351199900_DMM032219C14","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/j.1399-0004.2010.01515.x","article-title":"Contribution of VANGL2 mutations to isolated neural tube defects","volume":"80","author":"Kibar","year":"2011","journal-title":"Clin. Genet."},{"key":"2021042612351199900_DMM032219C15","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1242\/jcs.048074","article-title":"Vang-like protein 2 and Rac1 interact to regulate adherens junctions","volume":"123","author":"Lindqvist","year":"2010","journal-title":"J. Cell Sci."},{"key":"2021042612351199900_DMM032219C16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nature02677","article-title":"PTK7\/CCK-4 is a novel regulator of planar cell polarity in vertebrates","volume":"430","author":"Lu","year":"2004","journal-title":"Nature"},{"key":"2021042612351199900_DMM032219C17","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1242\/bio.20149589","article-title":"Shroom3 functions downstream of planar cell polarity to regulate myosin II distribution and cellular organization during neural tube closure","volume":"4","author":"Mcgreevy","year":"2015","journal-title":"Biol. Open"},{"key":"2021042612351199900_DMM032219C18","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/ncb2002","article-title":"Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure","volume":"12","author":"Merte","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"2021042612351199900_DMM032219C19","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/ncb2005","article-title":"An actomyosin-based barrier inhibits cell mixing at compartmental boundaries in Drosophila embryos","volume":"12","author":"Monier","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"2021042612351199900_DMM032219C20","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1136\/archdischild-2015-309226","article-title":"Prevention of neural tube defects in the UK: a missed opportunity","volume":"101","author":"Morris","year":"2016","journal-title":"Arch. Dis. Child."},{"key":"2021042612351199900_DMM032219C21","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"2021042612351199900_DMM032219C22","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1242\/dev.145904","article-title":"Neural tube closure: cellular, molecular and biomechanical mechanisms","volume":"144","author":"Nikolopoulou","year":"2017","journal-title":"Development"},{"key":"2021042612351199900_DMM032219C23","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1016\/j.cell.2012.04.021","article-title":"Planar cell polarity links axes of spatial dynamics in neural-tube closure","volume":"149","author":"Nishimura","year":"2012","journal-title":"Cell"},{"key":"2021042612351199900_DMM032219C24","doi-asserted-by":"publisher","first-page":"1880","DOI":"10.1038\/s41598-017-01971-2","article-title":"A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin","volume":"7","author":"Oozeer","year":"2017","journal-title":"Sci. Rep."},{"key":"2021042612351199900_DMM032219C25","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.ydbio.2015.06.013","article-title":"The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic development","volume":"408","author":"Ossipova","year":"2015","journal-title":"Dev. Biol."},{"key":"2021042612351199900_DMM032219C26","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1242\/bio.201511676","article-title":"Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling","volume":"4","author":"Ossipova","year":"2015","journal-title":"Biol. Open"},{"key":"2021042612351199900_DMM032219C27","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.ydbio.2017.07.020","article-title":"hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus","volume":"430","author":"Prager","year":"2017","journal-title":"Dev. Biol."},{"key":"2021042612351199900_DMM032219C28","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/978-1-61779-510-7_11","article-title":"Convergent extension analysis in mouse whole embryo culture","volume":"839","author":"Pryor","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"2021042612351199900_DMM032219C29","doi-asserted-by":"publisher","first-page":"e1004871","DOI":"10.1371\/journal.pgen.1004871","article-title":"Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development","volume":"10","author":"Ramsbottom","year":"2014","journal-title":"PLoS Genet."},{"key":"2021042612351199900_DMM032219C30","doi-asserted-by":"publisher","first-page":"e13273","DOI":"10.7554\/eLife.13273","article-title":"Regulation of cell protrusions by small GTPases during fusion of the neural folds","volume":"5","author":"Rolo","year":"2016","journal-title":"eLife"},{"key":"2021042612351199900_DMM032219C31","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/(SICI)1096-9861(19970519)381:4&lt;473::AID-CNE7&gt;3.0.CO;2-#","article-title":"Role of nonrandomly oriented cell division in shaping and bending of the neural plate","volume":"381","author":"Sausedo","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"2021042612351199900_DMM032219C32","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"2021042612351199900_DMM032219C33","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1136\/jmg.32.3.205","article-title":"Further evidence for an intermittent pattern of neural tube closure in humans","volume":"32","author":"Seller","year":"1995","journal-title":"J. Med. Genet."},{"key":"2021042612351199900_DMM032219C34","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1002\/ajmg.1320470528","article-title":"Evidence for multi-site closure of the neural tube in humans","volume":"47","author":"van Allen","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"2021042612351199900_DMM032219C35","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s004290100169","article-title":"Curly tail: a 50-year history of the mouse spina bifida model","volume":"203","author":"van Straaten","year":"2001","journal-title":"Anat Embryol. (Berl)"},{"key":"2021042612351199900_DMM032219C36","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.devcel.2014.02.007","article-title":"Distinct apical and basolateral mechanisms drive planar cell polarity-dependent convergent extension of the mouse neural plate","volume":"29","author":"Williams","year":"2014","journal-title":"Dev. Cell"},{"key":"2021042612351199900_DMM032219C37","doi-asserted-by":"publisher","first-page":"3203","DOI":"10.1242\/dev.008177","article-title":"Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling","volume":"134","author":"Ybot-Gonzalez","year":"2007","journal-title":"Development"},{"key":"2021042612351199900_DMM032219C38","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1242\/dev.000380","article-title":"Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure","volume":"134","author":"Ybot-Gonzalez","year":"2007","journal-title":"Development"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.032219","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.032219\/1861882\/dmm032219.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.032219\/2070012\/dmm_032219v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.032219\/2070012\/dmm_032219v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T21:42:09Z","timestamp":1621374129000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.032219\/265009\/Vangl2-disruption-alters-the-biomechanics-of-late"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,1]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1242\/dmm.032219","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2018,1,1]]},"article-number":"dmm.032219"}}