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

• DOI: 10.1016/j.devcel.2019.11.003
• Publication Date: 2019-12-05T16:16:15Z
• Authors: Talia Nasr; Pamela Mancini; Scott A. Rankin; Nicole A. Edwards; Zachary N. Agricola; Alan P. Kenny; Jessica L. Kinney; Keziah Daniels; Jon Vardanyan; Lu Han; Stephen L. Trisno; Sang-Wook Cha; James M. Wells; Matthew J. Kofron; Aaron M. Zorn
• Keywords: 0301 basic medicine; 0303 health sciences; Xenopus; Endoderm; Gene Expression Regulation, Developmental; Forkhead Transcription Factors; Endosomes; Mesoderm; 03 medical and health sciences; Esophagus; Mutation; Morphogenesis; Animals; Humans; Hedgehog Proteins; Digestive System; Body Patterning

SUMMARYThe 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 andXenopusto 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.Highlight bullet pointsThe Sox2+ esophagus and Nkx2-1+ trachea arise from the separation of a single foregut tube through a series of cellular events conserved in mouse andXenopusTracheoesophageal morphogenesis initiates with HH/Gli-dependent medial constriction of the gut tube mesenchyme at the Sox2-Nkx2-1 borderThe foregut epithelial walls fuse forming a transient septum co-expressing Sox2 and Nkx2-1Downstream of HH/Gli Rab11-dependent endosome-mediated epithelial remodeling and localized extracellular matrix degradation separate the esophagus and tracheaHH/Gli mutations reveal the cellular basis of tracheoesophageal birth defects