{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:21:22Z","timestamp":1791066082787,"version":"4.1.0"},"reference-count":54,"publisher":"The Company of Biologists","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,1,15]]},"abstract":"<jats:p>The progress of molecular genetics has enabled us to identify the genes responsible for congenital heart malformations. However, recent studies suggest that congenital heart diseases are induced not only by mutations in certain genes, but also by abnormal maternal factors. A high concentration of maternal retinoic acid (RA), the active derivative of vitamin A, is well known as a teratogenic agent that can cause developmental defects. Our previous studies have shown that the maternal administration of RA to mice within a narrow developmental window induces outflow tract (OFT) septum defects, a condition that closely resembles human transposition of the great arteries (TGA), although the responsible factors and pathogenic mechanisms of the TGA induced by RA remain unknown. We herein demonstrate that the expression of Tbx2 in the OFT myocardium is responsive to RA, and its downregulation is associated with abnormal OFT development. We found that RA could directly downregulate the Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter region, which is also required for the initiation of Tbx2 transcription during OFT development. Tgfb2 expression was also downregulated in the RA-treated OFT region and was upregulated by Tbx2 in a culture system. Moreover, defective epithelial-mesenchymal transition caused by the excess RA was rescued by the addition of Tgf\u03b22 in an organ culture system. These data suggest that RA signaling participates in the Tbx2 transcriptional mechanism during OFT development and that the Tbx2-Tgf\u03b22 cascade is one of the key pathways involved in inducing the TGA phenotype.<\/jats:p>","DOI":"10.1242\/dev.067058","type":"journal-article","created":{"date-parts":[[2011,12,20]],"date-time":"2011-12-20T07:29:13Z","timestamp":1324366153000},"page":"385-395","source":"Crossref","is-referenced-by-count":50,"title":["Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgf\u03b22 pathway"],"prefix":"10.1242","volume":"139","author":[{"given":"Masahide","family":"Sakabe","sequence":"first","affiliation":[{"name":"Division of Mammalian Development, National Institute of Genetics, 1111 Yata Mishima, Shizuoka 411-8540, Japan."},{"name":"Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Nara 634-8521, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kokubo","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development, National Institute of Genetics, 1111 Yata Mishima, Shizuoka 411-8540, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, Osaka 545-8585 City University, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Saga","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development, National Institute of Genetics, 1111 Yata Mishima, Shizuoka 411-8540, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042606324066200_R1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1161\/01.RES.0000202800.85341.6e","article-title":"Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries","volume":"98","author":"Bajolle","year":"2006","journal-title":"Circ. 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