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Dev Cell January 1, 2019; 51 (6): 665-674.e6.

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

Nasr T , Mancini P , Rankin SA , Edwards NA , Agricola ZN , Kenny AP , Kinney JL , Daniels K , Vardanyan J , Han L , Trisno SL , Cha SW , Wells JM , Kofron MJ , Zorn AM .

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.

PubMed ID: 31813796
Article link: Dev Cell
Grant support: [+]
Genes referenced: casp3.2 cdh1 cdh3 foxa2 foxf1 gli2 gli3 nkx2-1 nkx2-5 prkcz rab11a shh sox2
Antibodies: Cdh1 Ab10 Foxf1 Ab1 Nkx2-1 Ab3 Sox2 Ab4 Sox2 Ab5

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