Hedgehog regulation of epithelial cell state and morphogenesis in the larynx

The larynx enables speech while regulating swallowing and respiration. Larynx function hinges on the laryngeal epithelium which originates as part of the anterior foregut and undergoes extensive remodeling to separate from the esophagus and form vocal folds that interface with the adjacent trachea....

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Bibliographic Details
Published in:eLife 2022-11, Vol.11
Main Authors: Ramachandran, Janani, Zhou, Weiqiang, Bardenhagen, Anna E, Nasr, Talia, Yates, Ellen R, Zorn, Aaron M, Ji, Hongkai, Vokes, Steven A
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Birth defects
Cadherins
Cell death
Congenital defects
Development and progression
Developmental Biology
Epiglottis
Epithelial Cells
epithelial-to-mesenchymal transition
Epithelium
Esophagus
Etiology
Foregut
Genetics and Genomics
Hedgehog protein
Hedgehog Proteins
Larynx
larynx development
Mesenchyme
Mice
Morphogenesis
Mutants
Mutation
N-Cadherin
sonic hedgehog
Stem cells
vocal fold morophogenesis
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Summary:The larynx enables speech while regulating swallowing and respiration. Larynx function hinges on the laryngeal epithelium which originates as part of the anterior foregut and undergoes extensive remodeling to separate from the esophagus and form vocal folds that interface with the adjacent trachea. Here we find that sonic hedgehog (SHH) is essential for epithelial integrity in the mouse larynx as well as the anterior foregut. During larynx-esophageal separation, low expression marks specific domains of actively remodeling epithelium that undergo an epithelial-to-mesenchymal transition (EMT) characterized by the induction of N-Cadherin and movement of cells out of the epithelial layer. Consistent with a role for SHH signaling in regulating this process, mutants undergo an abnormal EMT throughout the anterior foregut and larynx, marked by a cadherin switch, movement out of the epithelial layer and cell death. Unexpectedly, mutant epithelial cells are replaced by a new population of FOXA2-negative cells that likely derive from adjacent pouch tissues and form a rudimentary epithelium. These findings have important implications for interpreting the etiology of HH-dependent birth defects within the foregut. We propose that SHH signaling has a default role in maintaining epithelial identity throughout the anterior foregut and that regionalized reductions in SHH trigger epithelial remodeling.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.77055