Isl1 Regulation of Nkx2.1 in the Early Foregut Epithelium Is Required for Trachea-Esophageal Separation and Lung Lobation

The esophagus and trachea arise from the dorsal and ventral aspects of the anterior foregut, respectively. Abnormal separation of the esophagus and trachea leads to the formation of the common birth defect esophageal atresia with/without tracheoesophageal fistula (EA/TEF). Although loss of multiple signaling molecules and transcription factors has been implicated in EA/TEF formation, the underlying cellular mechanisms remain unknown. Here, we combine Xenopus and mouse genetic models to identify the transcription factor Isl1 as a new player regulating trachea-esophageal separation. Significantly, we find that Isl1 orchestrates the separation process through modulating a specific epithelial progenitor cell population (Isl1+ Nkx2.1+ Sox2+) located at the dorsal-ventral boundary of the foregut. Our lineage tracing experiments show that this population contributes to both tracheal and esophageal epithelium. Moreover, Isl1 is required for the transcription of Nkx2.1 in this unique population. Finally, deletion of the chromosomal region spanning the ISL1 gene has been found in patients with abnormal trachea-esophageal separation. Our studies thus provide definitive evidence that ISL1 is a new player in the process of foregut morphogenesis, acting in a small progenitor population of boundary cells.