biostudies-literatureRamachandran JNICHD NIH HHSUniversity of Texas at AustinNHLBI NIH HHSNational Institutes of HealthNIH HHSe77055https://www.ebi.ac.uk/biostudies/studies/S-EPMC9718526biostudies-literatureUnknown11The 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 <i>Shh</i> 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, <i>Shh</i> 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, <i>Shh</i> 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.eLifeHedgehog regulation of epithelial cell state and morphogenesis in the larynx.PMC9718526F30 HL142201P01 HD093363Continuing Graduate FellowshipR01 HD073151Provost&apos;s Graduate Excellence FellowshipR01 HD090163RO1 HD093363Experiential Learning Summer ScholarshipRO1 HD090163TIDES Summer FellowshipNasr TJi HBardenhagen AEYates ERZorn AMZhou WRamachandran JVokes SAfalseHedgehog 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. 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 <i>Shh</i> 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, <i>Shh</i> 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, <i>Shh</i> 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.2022-01-01T00:00:00Z2022 Nov2026-05-28T01:10:47.127Z2025-04-19T22:48:22.895ZS-EPMC97185263639887810.7554/eLife.77055