Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity
- Genentech, United States
- University Medical Center Utrecht, Netherlands
- Baylor College of Medicine, United States
Abstract
Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD). The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in Drosophila melanogaster that allowed for rapid identification, validation and prioritization of COPD risk genes that were selected based on risk loci identified in human genome-wide association studies (GWAS) studies. Using intestinal barrier dysfunction in flies as a readout, our results validate the impact of candidate gene perturbations on epithelial barrier function in 56% of the cases, resulting in a prioritized target gene list. We further report the functional characterization in flies of one family of these genes, encoding for nicotinic acetylcholine receptor subunits (nAchR). We find that nAchR signaling in enterocytes of the fly gut promotes epithelial barrier function and epithelial homeostasis by regulating the production of the peritrophic matrix. Our findings identify COPD associated genes critical for epithelial barrier maintenance, and provide insight into the role of epithelial nAchR signaling for homeostasis.
Data availability
Sequencing data has been deposited in GEO under accession code GSE236071.
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Short-term depletion in Drosophila enteroendocrine cellsNCBI Gene Expression Omnibus, GSE236071.
Article and author information
Author details
Funding
Netherlands Organization for Scientific Research (184.034.014)
- Judith Klumperman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Bruno Lemaitre, École Polytechnique Fédérale de Lausanne, Switzerland
Version history
- Received: January 23, 2023
- Preprint posted: February 10, 2023 (view preprint)
- Accepted: October 31, 2023
- Accepted Manuscript published: December 8, 2023 (version 1)
- Version of Record published: January 3, 2024 (version 2)
Copyright
© 2023, Katheder 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.
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Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity
eLife 12:e86381.
https://doi.org/10.7554/eLife.86381
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