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We used blastocyst complementation to identify the role of NKX2\u20101 in the formation of the proximal\u2010peripheral boundary of the airways in mouse chimeric embryos.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>While Nkx2\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> mouse embryos form primordial tracheal cysts, peripheral pulmonary structures are entirely lacking in Nkx2\u20101<jats:sup>\u2212\/\u2212<\/jats:sup>mice. Complementation of Nkx2\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> embryos with NKX2\u20101\u2010sufficient embryonic stem cells (ESCs) enabled the formation of all tissue components of the peripheral lung but did not enhance ESC colonization of the most proximal regions of the airways. In chimeric mice, a precise boundary was formed between NKX2\u20101\u2010deficient basal cells co\u2010expressing SOX2 and SOX9 in large airways and ESC\u2010derived NKX2\u20101<jats:sup>+<\/jats:sup>SOX9<jats:sup>+<\/jats:sup> epithelial cells of smaller airways. NKX2\u20101\u2010sufficient ESCs were able to selectively complement peripheral, rather than most proximal regions of the airways. ESC complementation did not prevent ectopic expression of SOX9 but restored \u03b2\u2010catenin signaling in Nkx2\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> basal cells of large airways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>NKX2\u20101 and \u03b2\u2010catenin function in an epithelial cell\u2010autonomous manner to establish the proximal\u2010peripheral boundary along developing airways.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.298","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:59:00Z","timestamp":1610672340000},"page":"1001-1020","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Blastocyst complementation reveals that NKX2\u20101 establishes the proximal\u2010peripheral boundary of the airway epithelium"],"prefix":"10.1002","volume":"250","author":[{"given":"Enhong","family":"Li","sequence":"first","affiliation":[{"name":"Center 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