TY - JOUR TI - Hedgehog regulation of epithelial cell state and morphogenesis in the larynx AU - Ramachandran, Janani AU - Zhou, Weiqiang AU - Bardenhagen, Anna E AU - Nasr, Talia AU - Yates, Ellen R AU - Zorn, Aaron M AU - Ji, Hongkai AU - Vokes, Steven A A2 - Bronner, Marianne E A2 - Manley, Nancy VL - 11 PY - 2022 DA - 2022/11/18 SP - e77055 C1 - eLife 2022;11:e77055 DO - 10.7554/eLife.77055 UR - https://doi.org/10.7554/eLife.77055 AB - 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 Shh 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, Shh 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, Shh 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. KW - larynx development KW - foregut KW - epithelial-to-mesenchymal transition KW - sonic hedgehog KW - vocal fold morophogenesis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -