{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:55:38Z","timestamp":1778658938157,"version":"3.51.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Wnt signaling has been classified as canonical Wnt\/\u03b2-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor\u2013related protein Lrp6 is crucial for the activation of the Wnt\/\u03b2-catenin pathway, but its function in Wnt\/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26m1Jus) and in human NTDs. We demonstrate that Skax26m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26-Jus genetically interacts with a PCP mutant (Vangl2Lp) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells\u2019 polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.<\/jats:p>","DOI":"10.1093\/hmg\/ddt558","type":"journal-article","created":{"date-parts":[[2013,11,8]],"date-time":"2013-11-08T02:41:42Z","timestamp":1383878502000},"page":"1687-1699","source":"Crossref","is-referenced-by-count":38,"title":["Novel mutations in <i>Lrp6<\/i> orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway"],"prefix":"10.1093","volume":"23","author":[{"given":"Redouane","family":"Allache","sequence":"first","affiliation":[{"name":"1 \u00a0CHU Sainte Justine Research Center and University of Montr\u00e9al, Montr\u00e9al, QC, CanadaH3T 1C5"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phanie","family":"Lachance","sequence":"additional","affiliation":[{"name":"1 \u00a0CHU Sainte Justine Research Center and University of Montr\u00e9al, Montr\u00e9al, QC, CanadaH3T 1C5"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie Claude","family":"Guyot","sequence":"additional","affiliation":[{"name":"1 \u00a0CHU Sainte Justine Research Center and University of Montr\u00e9al, Montr\u00e9al, QC, CanadaH3T 1C5"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"De Marco","sequence":"additional","affiliation":[{"name":"2 \u00a0U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova16147, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Merello","sequence":"additional","affiliation":[{"name":"2 \u00a0U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova16147, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica J.","family":"Justice","sequence":"additional","affiliation":[{"name":"3 \u00a0Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[{"name":"2 \u00a0U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova16147, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoha","family":"Kibar","sequence":"additional","affiliation":[{"name":"1 \u00a0CHU Sainte Justine Research Center and University of Montr\u00e9al, Montr\u00e9al, QC, CanadaH3T 1C5"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,11,7]]},"reference":[{"key":"2022050522015400300_DDT558C1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrm3470","article-title":"The complex world of WNT receptor signalling","volume":"13","author":"Niehrs","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2022050522015400300_DDT558C2","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1038\/jid.2008.445","article-title":"A Wnt survival guide: from flies to human disease","volume":"129","author":"Chien","year":"2009","journal-title":"J. Invest. Dermatol."},{"key":"2022050522015400300_DDT558C3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.4161\/org.7.3.18143","article-title":"Planar cell polarity in Drosophila","volume":"7","author":"Maung","year":"2011","journal-title":"Organogenesis"},{"key":"2022050522015400300_DDT558C4","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.neuro.29.051605.112933","article-title":"Noncanonical Wnt signaling and neural polarity","volume":"29","author":"Montcouquiol","year":"2006","journal-title":"Annu. Rev. Neurosci."},{"key":"2022050522015400300_DDT558C5","first-page":"3897","article-title":"Convergent extension: using collective cell migration and cell intercalation to shape embryos","volume":"139","author":"Tada","year":"2012","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C6","first-page":"647","article-title":"Tissue\/planar cell polarity in vertebrates: new insights and new questions","volume":"134","author":"Wang","year":"2007","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C7","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.semcdb.2009.09.004","article-title":"Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt\/PCP pathway","volume":"20","author":"Roszko","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"2022050522015400300_DDT558C8","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/ajmg.c.30054","article-title":"Neural tube closure and neural tube defects: studies in animal models reveal known knowns and known unknowns","volume":"135C","author":"Wallingford","year":"2005","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2022050522015400300_DDT558C9","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.spen.2009.06.001","article-title":"Genetic basis of neural tube defects","volume":"16","author":"Bassuk","year":"2009","journal-title":"Semin. Pediatr. Neurol."},{"key":"2022050522015400300_DDT558C10","doi-asserted-by":"crossref","first-page":"1222002","DOI":"10.1126\/science.1222002","article-title":"The continuing challenge of understanding, preventing, and treating neural tube defects","volume":"339","author":"Wallingford","year":"2013","journal-title":"Science"},{"key":"2022050522015400300_DDT558C11","doi-asserted-by":"crossref","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":"Birt. Defects Res. A. Clin. Mol. Teratol."},{"key":"2022050522015400300_DDT558C12","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ejrad.2003.10.015","article-title":"Imaging in spine and spinal cord malformations","volume":"50","author":"Rossi","year":"2004","journal-title":"Eur. J. Radiol."},{"key":"2022050522015400300_DDT558C13","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.abb.2011.12.019","article-title":"The many roles of PTK7: a versatile regulator of cell\u2013cell communication","volume":"524","author":"Peradziryi","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"2022050522015400300_DDT558C14","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1101\/gad.230402","article-title":"The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt\/JNK signaling","volume":"16","author":"Schwarz-Romond","year":"2002","journal-title":"Genes Dev."},{"key":"2022050522015400300_DDT558C15","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1073\/pnas.1013170108","article-title":"Rack1 is required for Vangl2 membrane localization and planar cell polarity signaling while attenuating canonical Wnt activity","volume":"108","author":"Li","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022050522015400300_DDT558C16","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1091\/mbc.e08-07-0711","article-title":"The extracellular domain of Lrp5\/6 inhibits noncanonical Wnt signaling in vivo","volume":"20","author":"Bryja","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"2022050522015400300_DDT558C17","first-page":"4095","article-title":"Lrp6 is required for convergent extension during Xenopus gastrulation","volume":"134","author":"Tahinci","year":"2007","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C18","first-page":"1663","article-title":"LDL receptor-related proteins 5 and 6 in Wnt\/beta-catenin signaling: arrows point the way","volume":"131","author":"He","year":"2004","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C19","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/35035124","article-title":"An LDL-receptor-related protein mediates Wnt signalling in mice","volume":"407","author":"Pinson","year":"2000","journal-title":"Nature"},{"key":"2022050522015400300_DDT558C20","first-page":"318","article-title":"Generation of Lrp6 conditional gene-targeting mouse line for modeling and dissecting multiple birth defects\/congenital anomalies","volume":"239","author":"Zhou","year":"2010","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"2022050522015400300_DDT558C21","first-page":"5469","article-title":"Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis","volume":"131","author":"Kokubu","year":"2004","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C22","first-page":"667","article-title":"Stringent requirement of a proper level of canonical WNT signalling activity for head formation in mouse embryo","volume":"138","author":"Fossat","year":"2011","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C23","doi-asserted-by":"crossref","first-page":"12843","DOI":"10.1073\/pnas.0501963102","article-title":"Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6","volume":"102","author":"Carter","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022050522015400300_DDT558C24","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.modgep.2005.11.015","article-title":"Novel lethal mouse mutants produced in balancer chromosome screens","volume":"6","author":"Hentges","year":"2006","journal-title":"Gene Expr. Patterns GEP"},{"key":"2022050522015400300_DDT558C25","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/90081","article-title":"Ltap, a mammalian homolog of Drosophila Strabismus\/Van Gogh, is altered in the mouse neural tube mutant Loop-tail","volume":"28","author":"Kibar","year":"2001","journal-title":"Nat. Genet."},{"key":"2022050522015400300_DDT558C26","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.semcdb.2013.03.012","article-title":"Revisiting planar cell polarity in the inner ear","volume":"24","author":"Ezan","year":"2013","journal-title":"Semin. Cell Dev. Biol."},{"key":"2022050522015400300_DDT558C27","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature01618","article-title":"Identification of Vangl2 and Scrb1 as planar polarity genes in mammals","volume":"423","author":"Montcouquiol","year":"2003","journal-title":"Nature"},{"key":"2022050522015400300_DDT558C28","doi-asserted-by":"crossref","first-page":"a003376","DOI":"10.1101\/cshperspect.a003376","article-title":"Planar cell polarity: keeping hairs straight is not so simple","volume":"2","author":"McNeill","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2022050522015400300_DDT558C29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/BF00540233","article-title":"Cephaloceles: clinical and neuroradiological appearance. associated cerebral malformations","volume":"25","author":"Diebler","year":"1983","journal-title":"Neuroradiology"},{"key":"2022050522015400300_DDT558C30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/35077108","article-title":"LDL-receptor-related protein 6 is a receptor for Dickkopf proteins","volume":"411","author":"Mao","year":"2001","journal-title":"Nature"},{"key":"2022050522015400300_DDT558C31","first-page":"4295","article-title":"Wise, a context-dependent activator and inhibitor of Wnt signalling","volume":"130","author":"Itasaki","year":"2003","journal-title":"Dev. Camb. Engl."},{"key":"2022050522015400300_DDT558C32","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1101\/gad.406007","article-title":"Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt\/beta catenin and Wnt\/PCP activities, through interaction with the Dally-like homolog Knypek","volume":"21","author":"Caneparo","year":"2007","journal-title":"Genes Dev."},{"key":"2022050522015400300_DDT558C33","doi-asserted-by":"crossref","first-page":"4267","DOI":"10.1093\/hmg\/ddt277","article-title":"LRP6 Exerts non-canonical effects on Wnt signaling during neural tube closure","volume":"22","author":"Gray","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2022050522015400300_DDT558C34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/hmg\/ddg014","article-title":"Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse","volume":"12","author":"Murdoch","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2022050522015400300_DDT558C35","doi-asserted-by":"crossref","first-page":"e1000259","DOI":"10.1371\/journal.pgen.1000259","article-title":"Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development","volume":"4","author":"Etheridge","year":"2008","journal-title":"PLoS Genet."},{"key":"2022050522015400300_DDT558C36","doi-asserted-by":"crossref","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":"2022050522015400300_DDT558C37","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1056\/NEJMoa060651","article-title":"Mutations in VANGL1 associated with neural-tube defects","volume":"356","author":"Kibar","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"2022050522015400300_DDT558C38","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/humu.21589","article-title":"Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects","volume":"32","author":"Bosoi","year":"2011","journal-title":"Hum. Mutat."},{"key":"2022050522015400300_DDT558C39","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/humu.21643","article-title":"FZD6 is a novel gene for human neural tube defects","volume":"33","author":"De Marco","year":"2012","journal-title":"Hum. Mutat."},{"key":"2022050522015400300_DDT558C40","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1093\/hmg\/ddr359","article-title":"Mutations in the planar cell polarity gene, Fuzzy, are associated with neural tube defects in humans","volume":"20","author":"Seo","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2022050522015400300_DDT558C41","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/bdra.23002","article-title":"Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis","volume":"94","author":"Allache","year":"2012","journal-title":"Birt. Defects Res. A. Clin. Mol. Teratol."},{"key":"2022050522015400300_DDT558C42","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/humu.21662","article-title":"Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis","volume":"33","author":"Robinson","year":"2012","journal-title":"Hum. Mutat."},{"key":"2022050522015400300_DDT558C43","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1083\/jcb.200307181","article-title":"When Wnts antagonize Wnts","volume":"162","author":"Weidinger","year":"2003","journal-title":"J. Cell Biol."},{"key":"2022050522015400300_DDT558C44","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1083\/jcb.200303107","article-title":"Wnt-5\/pipetail functions in vertebrate axis formation as a negative regulator of Wnt\/beta-catenin activity","volume":"162","author":"Westfall","year":"2003","journal-title":"J. Cell Biol."},{"key":"2022050522015400300_DDT558C45","first-page":"237","article-title":"Genetic interaction between Lrp6 and Wnt5a during mouse development","volume":"239","author":"Andersson","year":"2010","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"2022050522015400300_DDT558C46","doi-asserted-by":"crossref","first-page":"1709.e9","DOI":"10.1016\/j.neurobiolaging.2012.11.004","article-title":"A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease","volume":"34","author":"Alarc\u00f3n","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"2022050522015400300_DDT558C47","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1126\/science.1136370","article-title":"LRP6 Mutation in a family with early coronary disease and metabolic risk factors","volume":"315","author":"Mani","year":"2007","journal-title":"Science"},{"key":"2022050522015400300_DDT558C48","first-page":"839","article-title":"A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene","volume":"240","author":"Guyot","year":"2011","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"2022050522015400300_DDT558C49","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nmeth1010","article-title":"Harnessing homologous recombination in vitro to generate recombinant DNA via SLIC","volume":"4","author":"Li","year":"2007","journal-title":"Nat. Methods"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/23\/7\/1687\/43557395\/hmg_23_7_1687.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/23\/7\/1687\/43557395\/hmg_23_7_1687.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T22:03:31Z","timestamp":1651788211000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/23\/7\/1687\/652887"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,7]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2013,11,7]]},"published-print":{"date-parts":[[2014,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddt558","relation":{},"ISSN":["1460-2083","0964-6906"],"issn-type":[{"value":"1460-2083","type":"electronic"},{"value":"0964-6906","type":"print"}],"subject":[],"published-other":{"date-parts":[[2014,4,1]]},"published":{"date-parts":[[2013,11,7]]}}}