{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T03:54:17Z","timestamp":1783396457555,"version":"3.54.6"},"reference-count":113,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0400679"],"award-info":[{"award-number":["G0400679"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Nonsyndromic clefts of the lip and palate are common birth defects resulting from gene-gene and gene-environment interactions. MSX1 mutations have been linked to orofacial clefting and we show here that Msx1 deficiency causes a growth defect of the medial nasal process (Mnp) in mouse embryos. While this defect alone does not disrupt lip formation, Msx1-deficient embryos develop a cleft lip when the mother is transiently exposed to reduced oxygen levels or to Phenytoin, a drug known to cause embryonic hypoxia. In the absence of interacting environmental factors, the Mnp growth defect caused by Msx1-deficiency is modified by a Pax9-dependent \u201cmorphogenetic regulation\u201d, which modulates Mnp shape, rescues lip formation and involves a localised abrogation of Bmp4-mediated repression of Pax9. Analyses of GWAS data revealed a genome-wide significant association of a Gene Ontology morphogenesis term (including assigned roles of MSX1, MSX2, PAX9, BMP4, GREM1) specifically for nonsyndromic cleft lip with cleft palate. Our data indicate that MSX1 mutations may increase the risk for cleft lip formation by interacting with an impaired morphogenetic regulation that adjusts Mnp shape, or through interactions that inhibit Mnp growth.<\/jats:p>","DOI":"10.1242\/dev.189175","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T13:42:28Z","timestamp":1590673348000},"source":"Crossref","is-referenced-by-count":21,"title":["<i>Msx1<\/i> deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development"],"prefix":"10.1242","author":[{"given":"Mitsushiro","family":"Nakatomi","sequence":"first","affiliation":[{"name":"Biosciences Institute, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK"},{"name":"Division of Anatomy, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin U.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Knapp","sequence":"additional","affiliation":[{"name":"Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Kist","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK"},{"name":"School of Dental Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Lisgo","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Ohshima","sequence":"additional","affiliation":[{"name":"Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Mangold","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2226-0749","authenticated-orcid":false,"given":"Heiko","family":"Peters","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042700573579400_DEV189175C1","doi-asserted-by":"publisher","first-page":"11616","DOI":"10.1038\/ncomms11616","article-title":"A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation","volume":"7","author":"Adhikari","year":"2016","journal-title":"Nat. Commun."},{"key":"2021042700573579400_DEV189175C2","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/bjc.1995.429","article-title":"Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver","volume":"72","author":"Arteel","year":"1995","journal-title":"Br. J. Cancer"},{"key":"2021042700573579400_DEV189175C3","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/tera.1026","article-title":"Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage","volume":"63","author":"Azarbayjani","year":"2001","journal-title":"Teratology"},{"key":"2021042700573579400_DEV189175C4","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1111\/j.1742-7843.2006.pto_416.x","article-title":"Increased susceptibility to phenytoin teratogenicity: excessive generation of reactive oxygen species or impaired antioxidant defense?","volume":"99","author":"Azarbayjani","year":"2006","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"2021042700573579400_DEV189175C5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/gepi.1039","article-title":"Testing candidate genes for non-syndromic oral clefts using a case-parent trio design","volume":"22","author":"Beaty","year":"2002","journal-title":"Genet. Epidemiol."},{"key":"2021042700573579400_DEV189175C6","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/ng.580","article-title":"A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4","volume":"42","author":"Beaty","year":"2010","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C7","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/ng.333","article-title":"Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24","volume":"41","author":"Birnbaum","year":"2009","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C8","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1038\/ejhg.2011.110","article-title":"Genetic determination of human facial morphology: links between cleft-lips and normal variation","volume":"19","author":"Boehringer","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C9","first-page":"113","article-title":"Morphogenesis of hypoxia-induced cleft lip in CL\/Fr mice","volume":"2","author":"Bronsky","year":"1986","journal-title":"J. Craniofac. Genet. Dev. Biol. Suppl."},{"key":"2021042700573579400_DEV189175C10","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1093\/hmg\/ddy402","article-title":"Genomic analyses in African populations identify novel risk loci for cleft palate","volume":"28","author":"Butali","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2021042700573579400_DEV189175C11","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/ajmg.a.20517","article-title":"Limb deficiency defects, MSX1, and exposure to tobacco smoke","volume":"125A","author":"Carmichael","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042700573579400_DEV189175C12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/(SICI)1096-8628(19990903)86:1&lt;9::AID-AJMG3&gt;3.0.CO;2-X","article-title":"Altitude as a risk factor for congenital anomalies","volume":"86","author":"Castilla","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"2021042700573579400_DEV189175C13","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1186\/s12864-018-4865-9","article-title":"Identification of five novel genetic loci related to facial morphology by genome-wide association studies","volume":"19","author":"Cha","year":"2018","journal-title":"BMC Genomics"},{"key":"2021042700573579400_DEV189175C14","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1002\/dvdy.20833","article-title":"Recent advances in craniofacial morphogenesis","volume":"235","author":"Chai","year":"2006","journal-title":"Dev. Dyn."},{"key":"2021042700573579400_DEV189175C15","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1242\/dev.122.10.3035","article-title":"Msx1 controls inductive signaling in mammalian tooth morphogenesis","volume":"122","author":"Chen","year":"1996","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C16","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41588-018-0057-4","article-title":"Genome-wide mapping of global-to-local genetic effects on human facial shape","volume":"50","author":"Claes","year":"2018","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C17","doi-asserted-by":"publisher","first-page":"e1006174","DOI":"10.1371\/journal.pgen.1006174","article-title":"Genomewide association study of African children identifies association of SCHIP1 and PDE8A with facial size and shape","volume":"12","author":"Cole","year":"2016","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C18","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.taap.2003.07.002","article-title":"Teratogenicity by the hERG potassium channel blocking drug almokalant: use of hypoxia marker gives evidence for a hypoxia-related mechanism mediated via embryonic arrhythmia","volume":"193","author":"Danielsson","year":"2003","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2021042700573579400_DEV189175C19","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1002\/bdra.20124","article-title":"Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism","volume":"73","author":"Danielsson","year":"2005","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"2021042700573579400_DEV189175C20","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.eplepsyres.2004.10.002","article-title":"Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents","volume":"63","author":"Danielsson","year":"2005","journal-title":"Epilepsy Res."},{"key":"2021042700573579400_DEV189175C21","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.reprotox.2007.04.005","article-title":"Embryonic cardiac arrhythmia and generation of reactive oxygen species: common teratogenic mechanism for IKr blocking drugs","volume":"24","author":"Danielsson","year":"2007","journal-title":"Reprod. Toxicol."},{"key":"2021042700573579400_DEV189175C22","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"2021042700573579400_DEV189175C23","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/j.devcel.2009.11.008","article-title":"The role of hypoxia in development of the Mammalian embryo","volume":"17","author":"Dunwoodie","year":"2009","journal-title":"Dev. Cell"},{"key":"2021042700573579400_DEV189175C24","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1002\/gepi.10255","article-title":"Family-based analysis of MSX1 haplotypes for association with oral clefts","volume":"25","author":"Fallin","year":"2003","journal-title":"Genet. Epidemiol."},{"key":"2021042700573579400_DEV189175C25","doi-asserted-by":"publisher","first-page":"13981","DOI":"10.18632\/oncotarget.24238","article-title":"Prevalence of non-syndromic orofacial clefts: based on 15,094,978 Chinese perinatal infants","volume":"9","author":"Fan","year":"2018","journal-title":"Oncotarget"},{"key":"2021042700573579400_DEV189175C26","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.devcel.2011.08.005","article-title":"A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis","volume":"21","author":"Ferretti","year":"2011","journal-title":"Dev. Cell"},{"key":"2021042700573579400_DEV189175C27","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1177\/0022034518777460","article-title":"Patterns of dental agenesis highlight the nature of the causative mutated genes","volume":"97","author":"Fournier","year":"2018","journal-title":"J. Dent. Res."},{"key":"2021042700573579400_DEV189175C28","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1177\/0022034517724145","article-title":"Vax1 plays an indirect role in the etiology of murine cleft palate","volume":"96","author":"Geoghegan","year":"2017","journal-title":"J. Dent. Res."},{"key":"2021042700573579400_DEV189175C29","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1046\/j.1432-0436.2003.710304.x","article-title":"Bmp4 gene is expressed at the putative site of fusion in the midfacial region","volume":"71","author":"Gong","year":"2003","journal-title":"Differentiation"},{"key":"2021042700573579400_DEV189175C30","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1177\/0022034516657003","article-title":"Association studies and direct DNA sequencing implicate genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations","volume":"95","author":"Gowans","year":"2016","journal-title":"J. Dent. Res."},{"key":"2021042700573579400_DEV189175C31","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1177\/1055665618754948","article-title":"Novel GREM1 variations in sub-Saharan African patients with cleft lip and\/or cleft palate","volume":"55","author":"Gowans","year":"2018","journal-title":"Cleft Palate Craniofac. J."},{"key":"2021042700573579400_DEV189175C32","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.jpeds.2009.06.020","article-title":"A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24","volume":"155","author":"Grant","year":"2009","journal-title":"J. Pediatr."},{"key":"2021042700573579400_DEV189175C33","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1159\/000337523","article-title":"The mouse as a developmental model for cleft lip and palate research","volume":"16","author":"Gritli-Linde","year":"2012","journal-title":"Front. Oral Biol."},{"key":"2021042700573579400_DEV189175C34","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1111\/eos.12414","article-title":"MSH homeobox\u00a01 polymorphisms and the risk of non-syndromic orofacial clefts: a meta-analysis","volume":"126","author":"Gu","year":"2018","journal-title":"Eur. J. Oral Sci."},{"key":"2021042700573579400_DEV189175C35","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1002\/tera.1420280205","article-title":"Comparative teratogenicity of phenytoin among several inbred strains of mice","volume":"28","author":"Hansen","year":"1983","journal-title":"Teratology"},{"key":"2021042700573579400_DEV189175C36","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.ydbio.2010.08.014","article-title":"Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis","volume":"347","author":"He","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042700573579400_DEV189175C37","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S1097-2765(00)80067-2","article-title":"The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities","volume":"1","author":"Hsu","year":"1998","journal-title":"Mol. Cell"},{"key":"2021042700573579400_DEV189175C112","doi-asserted-by":"publisher","author":"Huang","year":"2019","DOI":"10.1371\/journal.pgen.1008357"},{"key":"2021042700573579400_DEV189175C38","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1002\/(SICI)1096-8628(19980203)75:4&lt;419::AID-AJMG14&gt;3.0.CO;2-R","article-title":"Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency","volume":"75","author":"Hwang","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"2021042700573579400_DEV189175C39","doi-asserted-by":"publisher","first-page":"502","DOI":"10.3389\/fgene.2018.00502","article-title":"Six NSCL\/P loci show associations with normal-range craniofacial variation","volume":"9","author":"Indencleef","year":"2018","journal-title":"Front. Genet."},{"key":"2021042700573579400_DEV189175C40","doi-asserted-by":"publisher","first-page":"4937","DOI":"10.1242\/dev.02072","article-title":"Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest","volume":"132","author":"Ishii","year":"2005","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C41","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/j.1600-0722.2010.00729.x","article-title":"MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip\/palate","volume":"118","author":"Jagom\u00e4gi","year":"2010","journal-title":"Eur. J. Oral Sci."},{"key":"2021042700573579400_DEV189175C42","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1136\/jmg.40.6.399","article-title":"Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate","volume":"40","author":"Jezewski","year":"2003","journal-title":"J. Med. Genet."},{"key":"2021042700573579400_DEV189175C43","doi-asserted-by":"publisher","first-page":"3819","DOI":"10.1242\/dev.157750","article-title":"Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero","volume":"144","author":"Jia","year":"2017","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C44","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1002\/dvg.20295","article-title":"Derivation of a mouse model for conditional inactivation of Pax9","volume":"45","author":"Kist","year":"2007","journal-title":"Genesis"},{"key":"2021042700573579400_DEV189175C45","doi-asserted-by":"publisher","first-page":"e1004709","DOI":"10.1371\/journal.pgen.1004709","article-title":"The formation of endoderm-derived taste sensory organs requires a Pax9-dependent expansion of embryonic taste bud progenitor cells","volume":"10","author":"Kist","year":"2014","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C46","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1002\/dvdy.24341","article-title":"Toward an orofacial gene regulatory network","volume":"245","author":"Kousa","year":"2016","journal-title":"Dev. Dyn."},{"key":"2021042700573579400_DEV189175C113","doi-asserted-by":"publisher","author":"Kurosaka","year":"2014","DOI":"10.1371\/journal.pgen.1008357"},{"key":"2021042700573579400_DEV189175C47","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/s41559-019-0865-7","article-title":"The evolutionary history of the human face","volume":"3","author":"Lacruz","year":"2019","journal-title":"Nat. Ecol. Evol."},{"key":"2021042700573579400_DEV189175C48","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1023\/A:1008868325009","article-title":"Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase","volume":"7","author":"Lallemand","year":"1998","journal-title":"Transgenic Res."},{"key":"2021042700573579400_DEV189175C49","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1242\/dev.01877","article-title":"Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development","volume":"132","author":"Lallemand","year":"2005","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C50","doi-asserted-by":"publisher","first-page":"2862","DOI":"10.1093\/hmg\/ddw104","article-title":"A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13","volume":"25","author":"Leslie","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021042700573579400_DEV189175C51","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1177\/0022034517719865","article-title":"Modulating Wnt signaling rescues palate morphogenesis in Pax9 mutant mice","volume":"96","author":"Li","year":"2017","journal-title":"J. Dent. Res."},{"key":"2021042700573579400_DEV189175C52","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1086\/301956","article-title":"Association of MSX1 and TGFB3 with nonsyndromic clefting in humans","volume":"63","author":"Lidral","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C53","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1242\/dev.01676","article-title":"Distinct functions for Bmp signaling in lip and palate fusion in mice","volume":"132","author":"Liu","year":"2005","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C54","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ajhg.2010.06.009","article-title":"A versatile gene-based test for genome-wide association studies","volume":"87","author":"Liu","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C55","doi-asserted-by":"publisher","first-page":"e1002932","DOI":"10.1371\/journal.pgen.1002932","article-title":"A genome-wide association study identifies five loci influencing facial morphology in Europeans","volume":"8","author":"Liu","year":"2012","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C56","doi-asserted-by":"publisher","first-page":"3055","DOI":"10.1242\/dev.063214","article-title":"Msx genes define a population of mural cell precursors required for head blood vessel maturation","volume":"138","author":"Lopes","year":"2011","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C57","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1038\/ng.2360","article-title":"Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci","volume":"44","author":"Ludwig","year":"2012","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C58","doi-asserted-by":"publisher","first-page":"e1005914","DOI":"10.1371\/journal.pgen.1005914","article-title":"Meta-analysis reveals genome-wide significance at 15q13 for nonsyndromic clefting of both the lip and the palate, and functional analyses implicate GREM1 as a plausible causative gene","volume":"12","author":"Ludwig","year":"2016","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C59","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1093\/hmg\/ddx012","article-title":"Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip\u00b1cleft palate and cleft palate only","volume":"26","author":"Ludwig","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2021042700573579400_DEV189175C60","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1242\/dev.111.2.269","article-title":"The homeobox gene Hox 7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro","volume":"111","author":"Mackenzie","year":"1991","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C61","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/ng.506","article-title":"Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate","volume":"42","author":"Mangold","year":"2010","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C62","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.molmed.2011.07.007","article-title":"Breakthroughs in the genetics of orofacial clefting","volume":"17","author":"Mangold","year":"2011","journal-title":"Trends Mol. Med."},{"key":"2021042700573579400_DEV189175C63","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/dvdy.8","article-title":"Systematic review of hormonal and genetic factors involved in the nonsyndromic disorders of the lower jaw","volume":"248","author":"Manocha","year":"2019","journal-title":"Dev. Dyn."},{"key":"2021042700573579400_DEV189175C64","doi-asserted-by":"publisher","first-page":"375","DOI":"10.3389\/fphys.2012.00375","article-title":"Wnt\/\u03b2-catenin signaling and Msx1 promote outgrowth of the maxillary prominences","volume":"3","author":"Medio","year":"2012","journal-title":"Front. Physiol."},{"key":"2021042700573579400_DEV189175C65","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1111\/joa.12182","article-title":"Exploratory genotype-phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and\/or palate","volume":"224","author":"Miller","year":"2014","journal-title":"J. Anat."},{"key":"2021042700573579400_DEV189175C66","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1126\/science.7221553","article-title":"Maternal hyperoxia greatly reduces the incidence of phenytoin-induced cleft lip and palate in A\/J mice","volume":"212","author":"Millicovsky","year":"1981","journal-title":"Science"},{"key":"2021042700573579400_DEV189175C67","doi-asserted-by":"publisher","first-page":"5722","DOI":"10.1073\/pnas.78.9.5722","article-title":"Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL\/Fr mice","volume":"78","author":"Millicovsky","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042700573579400_DEV189175C68","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1093\/aje\/153.10.1007","article-title":"Evaluation of two putative susceptibility loci for oral clefts in the Danish population","volume":"153","author":"Mitchell","year":"2001","journal-title":"Am. J. Epidemiol."},{"key":"2021042700573579400_DEV189175C69","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1016\/S0140-6736(09)60695-4","article-title":"Cleft lip and palate","volume":"374","author":"Mossey","year":"2009","journal-title":"Lancet"},{"key":"2021042700573579400_DEV189175C70","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/bdra.23000","article-title":"Effects of embryonic hypoxia on lip formation","volume":"94","author":"Nagaoka","year":"2012","journal-title":"Birth. Defects Res. A Clin. Mol. Teratol."},{"key":"2021042700573579400_DEV189175C71","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.ydbio.2010.01.031","article-title":"Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis","volume":"340","author":"Nakatomi","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042700573579400_DEV189175C72","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1006\/dbio.1995.1248","article-title":"Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1","volume":"170","author":"Neub\u00fcser","year":"1995","journal-title":"Dev. Biol."},{"key":"2021042700573579400_DEV189175C73","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/S0092-8674(00)80333-5","article-title":"Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation","volume":"90","author":"Neub\u00fcser","year":"1997","journal-title":"Cell"},{"key":"2021042700573579400_DEV189175C74","doi-asserted-by":"publisher","first-page":"18363","DOI":"10.1074\/jbc.M601543200","article-title":"Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development","volume":"281","author":"Ogawa","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021042700573579400_DEV189175C75","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1597\/06-097.1","article-title":"Association of MSX1 with nonsyndromic cleft lip and palate in a Colombian population","volume":"44","author":"Otero","year":"2007","journal-title":"Cleft Palate Craniofac. J."},{"key":"2021042700573579400_DEV189175C76","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1159\/000337617","article-title":"Roles of BMP signaling pathway in lip and palate development","volume":"16","author":"Parada","year":"2012","journal-title":"Front. Oral Biol."},{"key":"2021042700573579400_DEV189175C77","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.ajhg.2011.12.021","article-title":"Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position","volume":"90","author":"Paternoster","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C78","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1101\/gad.12.17.2735","article-title":"Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities","volume":"12","author":"Peters","year":"1998","journal-title":"Genes Dev."},{"key":"2021042700573579400_DEV189175C79","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/ng.3570","article-title":"Detection and interpretation of shared genetic influences on 42 human traits","volume":"48","author":"Pickrell","year":"2016","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C80","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15513815.2019.1666329","article-title":"Association of genetic polymorphisms of GREM1 gene with susceptibility to non-syndromic cleft lip with or without cleft palate in an Iranian population","volume":"25","author":"Rafighdoost","year":"2019","journal-title":"Fetal Pediatr. Pathol."},{"key":"2021042700573579400_DEV189175C81","doi-asserted-by":"publisher","first-page":"dmm037051","DOI":"10.1242\/dmm.037051","article-title":"Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models","volume":"12","author":"Reynolds","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"2021042700573579400_DEV189175C82","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/(SICI)1096-9926(199901)59:1&lt;39::AID-TERA9&gt;3.0.CO;2-7","article-title":"Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts","volume":"59","author":"Romitti","year":"1999","journal-title":"Teratology"},{"key":"2021042700573579400_DEV189175C83","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/ng0494-348","article-title":"Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development","volume":"6","author":"Satokata","year":"1994","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C84","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/74231","article-title":"Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation","volume":"24","author":"Satokata","year":"2000","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C85","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/ajmg.a.20424","article-title":"Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families","volume":"125A","author":"Schultz","year":"2004","journal-title":"Am. J. Med. Genet A"},{"key":"2021042700573579400_DEV189175C86","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1001\/archfaci.5.1.16","article-title":"Development of the upper lip","volume":"5","author":"Senders","year":"2003","journal-title":"Arch. Facial Plast. Surg."},{"key":"2021042700573579400_DEV189175C87","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.ejmg.2014.04.003","article-title":"Genetics of cleft lip and\/or cleft palate: association with other common anomalies","volume":"57","author":"Set\u00f3-Salvia","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"2021042700573579400_DEV189175C88","doi-asserted-by":"publisher","first-page":"e1006149","DOI":"10.1371\/journal.pgen.1006149","article-title":"Genome-wide association study reveals multiple loci influencing normal human facial morphology","volume":"12","author":"Shaffer","year":"2016","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C89","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/humu.21658","article-title":"VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans","volume":"33","author":"Slavotinek","year":"2012","journal-title":"Hum. Mutat."},{"key":"2021042700573579400_DEV189175C90","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1242\/dmm.011064","article-title":"The effect of hypoxia on facial shape variation and disease phenotypes in chicken embryos","volume":"6","author":"Smith","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"2021042700573579400_DEV189175C91","doi-asserted-by":"publisher","first-page":"6414","DOI":"10.1038\/ncomms7414","article-title":"Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate","volume":"6","author":"Sun","year":"2015","journal-title":"Nat. Commun."},{"key":"2021042700573579400_DEV189175C92","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1097\/01.GIM.0000127275.52925.05","article-title":"In a Vietnamese population, MSX1 variants contribute to cleft lip and palate","volume":"6","author":"Suzuki","year":"2004","journal-title":"Genet. Med."},{"key":"2021042700573579400_DEV189175C93","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.ajhg.2009.02.002","article-title":"Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip","volume":"84","author":"Suzuki","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C94","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1002\/dvdy.24368","article-title":"Molecular mechanisms of midfacial developmental defects","volume":"245","author":"Suzuki","year":"2016","journal-title":"Dev. Dyn."},{"key":"2021042700573579400_DEV189175C95","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cardiores.2003.12.026","article-title":"Pharmacology of cardiac potassium channels","volume":"62","author":"Tamargo","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"2021042700573579400_DEV189175C96","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/(SICI)1096-8628(19980113)75:2&lt;126::AID-AJMG2&gt;3.0.CO;2-R","article-title":"Classification and birth prevalence of orofacial clefts","volume":"75","author":"Tolarov\u00e1","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"2021042700573579400_DEV189175C97","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1007\/s10038-006-0006-4","article-title":"MSX1 mutations contribute to nonsyndromic cleft lip in a Thai population","volume":"51","author":"Tongkobpetch","year":"2006","journal-title":"J. Hum. Genet."},{"key":"2021042700573579400_DEV189175C98","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.semcdb.2005.06.007","article-title":"Specification of neural crest cell formation and migration in mouse embryos","volume":"16","author":"Trainor","year":"2005","journal-title":"Semin. Cell. Dev. Biol."},{"key":"2021042700573579400_DEV189175C99","doi-asserted-by":"publisher","first-page":"R56","DOI":"10.1186\/bcr2615","article-title":"ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67","volume":"12","author":"Tuominen","year":"2010","journal-title":"Breast Cancer Res."},{"key":"2021042700573579400_DEV189175C100","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/74155","article-title":"MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans","volume":"24","author":"van den Boogaard","year":"2000","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C101","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s00439-008-0569-6","article-title":"The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts","volume":"124","author":"van den Boogaard","year":"2008","journal-title":"Hum. Genet."},{"key":"2021042700573579400_DEV189175C102","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/ng0896-417","article-title":"A human MSX1 homeodomain missense mutation causes selective tooth agenesis","volume":"13","author":"Vastardis","year":"1996","journal-title":"Nat. Genet."},{"key":"2021042700573579400_DEV189175C103","doi-asserted-by":"publisher","first-page":"e64","DOI":"10.1371\/journal.pgen.0010064","article-title":"Medical sequencing of candidate genes for nonsyndromic cleft lip and palate","volume":"1","author":"Vieira","year":"2005","journal-title":"PLoS Genet."},{"key":"2021042700573579400_DEV189175C104","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1111\/jop.12662","article-title":"Association between a single-nucleotide polymorphism in the GREM1 gene and non-syndromic orofacial cleft in the Chinese population","volume":"47","author":"Wang","year":"2018","journal-title":"J. Oral Pathol. Med."},{"key":"2021042700573579400_DEV189175C105","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/bdrc.20102","article-title":"The effect of hypoxia in development","volume":"81","author":"Webster","year":"2007","journal-title":"Birth Defects Res. C Embryo. Today"},{"key":"2021042700573579400_DEV189175C106","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.2174\/138161206776389868","article-title":"The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin","volume":"12","author":"Webster","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"2021042700573579400_DEV189175C107","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3389\/fgene.2018.00413","article-title":"Non-syndromic cleft lip and palate polymorphisms affect normal lip morphology","volume":"9","author":"Wilson-Nagrani","year":"2018","journal-title":"Front. Genet."},{"key":"2021042700573579400_DEV189175C108","doi-asserted-by":"publisher","first-page":"e49898","DOI":"10.7554\/eLife.49898","article-title":"Novel genetic loci affecting facial shape variation in humans","volume":"8","author":"Xiong","year":"2019","journal-title":"eLife"},{"key":"2021042700573579400_DEV189175C109","doi-asserted-by":"publisher","first-page":"14364","DOI":"10.1038\/ncomms14364","article-title":"Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"2021042700573579400_DEV189175C110","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1242\/dev.129.17.4135","article-title":"Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis","volume":"129","author":"Zhang","year":"2002","journal-title":"Development"},{"key":"2021042700573579400_DEV189175C111","doi-asserted-by":"publisher","first-page":"4709","DOI":"10.1242\/dev.099028","article-title":"Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis","volume":"140","author":"Zhou","year":"2013","journal-title":"Development"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.189175","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.189175\/1970862\/dev189175.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.189175\/2064804\/dev_189175v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.189175\/2064804\/dev_189175v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T22:53:11Z","timestamp":1621378391000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.189175\/266910\/Msx1-deficiency-interacts-with-hypoxia-and-induces"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":113,"URL":"https:\/\/doi.org\/10.1242\/dev.189175","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,1]]},"article-number":"dev.189175"}}