Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog-Gli Is Required for Tracheoesophageal Separation

The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Mutations in key signaling pathways such as Hedgehog (HH)/Gli can disrupt tracheoesophageal (TE) morphogenesis and cause life-threatening birth defects (TEDs); however, the underlying cellular mechanisms are unknown. Here, we use mouse and Xenopus to define the HH/Gli-dependent processes orchestrating TE morphogenesis. We show that downstream of Gli the Foxf1+ splanchnic mesenchyme promotes medial constriction of the foregut at the boundary between the presumptive Sox2+ esophageal and Nkx2-1+ tracheal epithelium. We identify a unique boundary epithelium co-expressing Sox2 and Nkx2-1 that fuses to form a transient septum. Septum formation and resolution into distinct trachea and esophagus requires endosome-mediated epithelial remodeling involving the small GTPase Rab11 and localized extracellular matrix degradation. These are disrupted in Gli-deficient embryos. This work provides a new mechanistic framework for TE morphogenesis and informs the cellular basis of human TEDs. [Display omitted] •The Sox2+ esophagus and Nkx2-1+ trachea arise from the separation of the foregut•HH/Gli-dependent medial constriction of the foregut initiates morphogenesis•Rab11-dependent epithelial remodeling and ECM degradation separate the foregut•HH/Gli mutations reveal the cellular basis of tracheoesophageal birth defects The etiology of tracheoesophageal birth defects is unknown. Nasr et al. define the conserved cellular mechanisms of foregut morphogenesis in Xenopus and mouse and show how disruption of Rab11-mediated epithelial remodeling downstream of Hedgehog/Gli signaling results in tracheoesophageal clefts similar to human patients.