Yap is a key regulator of tracheoesophageal separation during foregut development

Abstract

Separation of the anterior foregut into the esophagus and trachea involves dynamic cellular movement that requires the coordinated activity of multiple signaling pathways and transcription factors. Disruption of this process can result in esophageal atresia (EA) with or without tracheoesophageal fistula (TEF), manifesting in five major anatomical types (Types A-E). Here, we examine the role of the Hippo pathway effector Yes-associated protein (Yap) in foregut separation. Conditional deletion of Yap in the dorsal and medial portions of the anterior foregut endoderm leads to the formation of Type A EA/TEF, isolated EA. This separation defect only occurs in Sox2-CreER;Yaploxp/loxp but not in Shh-Cre;Yaploxp/loxp mutants. Our findings further reveal that Yap mutants exhibit a reduction in Sox2+ esophageal progenitor cells accompanied by the absence of the middle esophageal segment. Combined deletion of Yap and Taz (transcriptional coactivator with PDZ-binding motif) also results in isolated EA accompanied by severe craniofacial abnormalities. Therefore, loss of Yap causes a distinct Type A EA/TEF, which differs from existing mouse models of EA/TEF that predominantly exhibit the Type C phenotype. Our findings also suggest that epithelial cells at the dorsal-ventral boundary play a critical role in tracheoesophageal separation.