Hedgehog regulation of epithelial cell state and morphogenesis in the larynx
- The University of Texas at Austin, United States
- Johns Hopkins University, United States
- Cincinnati Children's Hospital Medical Center, United States
Abstract
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE190281.
-
Hedgehog signaling is essential to maintain epithelial identity during larynx and foregut morphogenesis.NCBI Gene Expression Omnibus, GSE190281.
Article and author information
Author details
Funding
National Institutes of Health (RO1 HD090163)
- Hongkai Ji
- Steven A Vokes
National Institutes of Health (RO1 HD093363)
- Aaron M Zorn
National Institutes of Health (F30 HL142201)
- Talia Nasr
University of Texas at Austin (Continuing Graduate Fellowship)
- Janani Ramachandran
University of Texas at Austin (Provost's Graduate Excellence Fellowship)
- Janani Ramachandran
University of Texas at Austin (TIDES Summer Fellowship)
- Anna E Bardenhagen
University of Texas at Austin (Experiential Learning Summer Scholarship)
- Ellen R Yates
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments involving mice were approved by the Institutional Animal Care and Use Committee at the University of Texas at Austin (protocol AUP-2019-00233).
Copyright
© 2022, Ramachandran et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 877
- views
-
- 145
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Hedgehog regulation of epithelial cell state and morphogenesis in the larynx
eLife 11:e77055.
https://doi.org/10.7554/eLife.77055
Further reading
-
- Developmental Biology
The formation of the mammalian brain requires regionalization and morphogenesis of the cranial neural plate, which transforms from an epithelial sheet into a closed tube that provides the structural foundation for neural patterning and circuit formation. Sonic hedgehog (SHH) signaling is important for cranial neural plate patterning and closure, but the transcriptional changes that give rise to the spatially regulated cell fates and behaviors that build the cranial neural tube have not been systematically analyzed. Here, we used single-cell RNA sequencing to generate an atlas of gene expression at six consecutive stages of cranial neural tube closure in the mouse embryo. Ordering transcriptional profiles relative to the major axes of gene expression predicted spatially regulated expression of 870 genes along the anterior-posterior and mediolateral axes of the cranial neural plate and reproduced known expression patterns with over 85% accuracy. Single-cell RNA sequencing of embryos with activated SHH signaling revealed distinct SHH-regulated transcriptional programs in the developing forebrain, midbrain, and hindbrain, suggesting a complex interplay between anterior-posterior and mediolateral patterning systems. These results define a spatiotemporally resolved map of gene expression during cranial neural tube closure and provide a resource for investigating the transcriptional events that drive early mammalian brain development.
-
- Developmental Biology
Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.
