{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:36:18Z","timestamp":1792665378829,"version":"4.5.0"},"reference-count":41,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":496,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K15836"],"award-info":[{"award-number":["16K15836"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H05687"],"award-info":[{"award-number":["15H05687"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008731","name":"Nakatomi Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007795","name":"Stowers Institute for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Cleft palate (CP) is one of the most common congenital craniofacial anomalies in humans and can be caused by either single or multiple genetic and environmental factor(s). With respect to environmental factors, excessive intake of vitamin A during early pregnancy is associated with increased incidence of CP in offspring both in humans and in animal models. Vitamin A is metabolized to retinoic acid (RA); however, the pathogenetic mechanism of CP caused by altered RA signaling during early embryogenesis is not fully understood. To investigate the detailed cellular and molecular mechanism of RA-induced CP, we administered all-trans RA to pregnant mice at embryonic day (E)8.5. In the RA-treated group, we observed altered expression of Sox10, which marks cranial neural crest cells (CNCCs). Disruption of Sox10 expression was also observed at E10.5 in the maxillary component of the first branchial arch, which gives rise to secondary palatal shelves. Moreover, we found significant elevation of CNCC apoptosis in RA-treated embryos. RNA-sequencing comparisons of RA-treated embryos compared to controls revealed alterations in Sonic hedgehog (Shh) signaling. More specifically, the expression of Shh and its downstream genes Ptch1 and Gli1 was spatiotemporally downregulated in the developing face of RA-treated embryos. Consistent with these findings, the incidence of CP in association with excessive RA signaling was reduced by administration of the Shh signaling agonist SAG (Smoothened agonist). Altogether, our results uncovered a novel mechanistic association between RA-induced CP with decreased Shh signaling and elevated CNCC apoptosis.<\/jats:p>","DOI":"10.1242\/dmm.040279","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T12:45:14Z","timestamp":1570193114000},"source":"Crossref","is-referenced-by-count":43,"title":["Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate"],"prefix":"10.1242","volume":"12","author":[{"given":"Qi","family":"Wang","sequence":"first","affiliation":[{"name":"Graduate School of Dentistry, Osaka University 1 Department of Orthodontics and Dentofacial Orthopedics , , Suita 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-5467","authenticated-orcid":false,"given":"Hiroshi","family":"Kurosaka","sequence":"additional","affiliation":[{"name":"Graduate School of Dentistry, Osaka University 1 Department of Orthodontics and Dentofacial Orthopedics , , Suita 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Osaka University 2 Department of Genome Informatics , , Suita 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Nakaya","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Osaka University 2 Department of Genome Informatics , , Suita 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Trainor","sequence":"additional","affiliation":[{"name":"Stowers Institute for Medical Research 3 , Kansas City, MO 64110 , USA"},{"name":"University of Kansas Medical Center 4 Department of Anatomy and Cell Biology , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-9643","authenticated-orcid":false,"given":"Takashi","family":"Yamashiro","sequence":"additional","affiliation":[{"name":"Graduate School of Dentistry, Osaka University 1 Department of Orthodontics and Dentofacial Orthopedics , , Suita 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,10,4]]},"reference":[{"key":"2024061302153481400_DMM040279C1","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/tera.1420420604","article-title":"Retinoic acid-induced alterations in the expression of growth factors in embryonic mouse palatal shelves","volume":"42","author":"Abbott","year":"1990","journal-title":"Teratology"},{"key":"2024061302153481400_DMM040279C2","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/tera.1420400602","article-title":"Etiology of retinoic acid-induced cleft palate varies with the embryonic stage","volume":"40","author":"Abbott","year":"1989","journal-title":"Teratology"},{"key":"2024061302153481400_DMM040279C3","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1111\/j.1753-4887.2011.00425.x","article-title":"Vitamin a and clefting: putative biological mechanisms","volume":"69","author":"Ackermans","year":"2011","journal-title":"Nutr. 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