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Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by <jats:italic>Sox2<\/jats:italic> and <jats:italic>Gata4<\/jats:italic>, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal\u2013distal segregation of <jats:italic>Sox2<\/jats:italic> and <jats:italic>Gata4<\/jats:italic> expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, <jats:italic>Gata4<\/jats:italic>-mediated expression of the morphogen <jats:italic>Fgf10<\/jats:italic> in the distal stomach and <jats:italic>Sox2<\/jats:italic>-mediated <jats:italic>Fgfr2<\/jats:italic> expression in the proximal stomach induce the intermediate regional activation of MAPK\/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.<\/jats:p>","DOI":"10.1038\/s41467-021-20906-0","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T11:06:41Z","timestamp":1611572801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Epithelial expression of Gata4 and Sox2 regulates specification of the squamous\u2013columnar junction via MAPK\/ERK signaling in mice"],"prefix":"10.1038","volume":"12","author":[{"given":"Nao","family":"Sankoda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Tanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akito","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Shibata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut","family":"Woltjen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Haga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiharu","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Mandai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0022-3947","authenticated-orcid":false,"given":"Takuya","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2463-1478","authenticated-orcid":false,"given":"Yasuhiro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Uemoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-4235","authenticated-orcid":false,"given":"Yoshiya","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,25]]},"reference":[{"key":"20906_CR1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/nrg2902","volume":"12","author":"C Dahmann","year":"2011","unstructured":"Dahmann, C., Oates, A. 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