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 trachea-esophageal separation leads to the common birth defect esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Yet the underlying cellular mechanisms remain unknown. Here, we combine Xenopus and mouse genetic models to identify that the transcription factor Isl1 orchestrates trachea-esophageal separation through modulating a specific epithelial progenitor cell population (midline epithelial cells [MECs], Isl1+ Nkx2.1+ Sox2+) located at the dorsal-ventral boundary of the foregut. Lineage tracing experiments show that MECs contribute to both tracheal and esophageal epithelium, and Isl1 is required for Nkx2.1 transcription in MECs. 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 critical player in the process of foregut morphogenesis, acting in a small progenitor population of boundary cells. • Isl1 disruption leads to abnormal trachea-esophageal separation in frog and mouse • Nkx2.1 lineage-derived respiratory cells contribute to the esophageal epithelium • A midline cell population is critical for trachea-esophageal separation • Isl1 regulates the transcription of Nkx2.1 in the midline epithelial progenitor cells The disease mechanism of the birth defect esophageal atresia with or without trachea-esophageal fistula remains largely unknown. Kim et al. used Xenopus and mouse genetic models to show that an Isl1-Nkx2.1 axis regulates a midline epithelial progenitor cell population that orchestrates trachea-esophageal separation. [ABSTRACT FROM AUTHOR]