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Dev Cell 2019 Dec 16;516:665-674.e6. doi: 10.1016/j.devcel.2019.11.003.
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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
PMC ID: PMC7895302
Article link: Dev Cell
Grant support: [+]

Species referenced: Xenopus
Genes referenced: casp3.2 cdh1 cdh3 fn1 foxa2 foxf1 gli2 gli3 nkx2-1 nkx2-5 prkci prkcz rab11a shh sox2 tec
Antibodies: Cdh1 Ab10 Foxf1 Ab1 Nkx2-1 Ab3 Sox2 Ab4 Sox2 Ab5
gRNAs referenced: rab11a gRNA1

Disease Ontology terms: esophageal atresia/tracheoesophageal fistula [+]
Phenotypes: Xla Wt + Doxycycline hyclate + Tg(hhex:rtTA;TRE:{dn}Rab11a-GFP) (Fig.2.I) [+]

Article Images: [+] show captions
References [+] :
Billmyre, One shall become two: Separation of the esophagus and trachea from the common foregut tube. 2015, Pubmed