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Dev Cell. 2019 Dec 16;51(6):665-674.e6. doi: 10.1016/j.devcel.2019.11.003. Epub 2019 Dec 5.

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

Author information

1
Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, and Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
2
Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, and Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
3
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
4
Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, and Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA. Electronic address: aaron.zorn@cchmc.org.

Abstract

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.

KEYWORDS:

EA/TEF; Sox2; esophageal atresia

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