Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity

  1. Nadja S Katheder
  2. Kristen C Browder
  3. Diana Chang
  4. Ann De Maziere
  5. Pekka Kujala
  6. Suzanne van Dijk
  7. Judith Klumperman
  8. Tzu-Chiao Lu
  9. Hongjie Li
  10. Zijuan Lai
  11. Dewakar Sangaraju
  12. Heinrich Jasper  Is a corresponding author
  1. Genentech, United States
  2. University Medical Center Utrecht, Netherlands
  3. 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.

The following data sets were generated

Article and author information

Author details

  1. Nadja S Katheder

    Regenerative Medicine, Genentech, South San Francisco, United States
    Competing interests
    Nadja S Katheder, is affiliated with Genentech. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0460-0938
  2. Kristen C Browder

    Regenerative Medicine, Genentech, South San Francisco, United States
    Competing interests
    Kristen C Browder, is affiliated with Genentech. The author has no financial interests to declare..
  3. Diana Chang

    Human Genetics, Genentech, South San Francisco, United States
    Competing interests
    Diana Chang, is affiliated with Genentech. The author has no financial interests to declare..
  4. Ann De Maziere

    Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8070-5104
  5. Pekka Kujala

    Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  6. Suzanne van Dijk

    Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  7. Judith Klumperman

    Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  8. Tzu-Chiao Lu

    Huffington Center on Aging, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Hongjie Li

    Huffington Center on Aging, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Zijuan Lai

    Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, United States
    Competing interests
    Zijuan Lai, is affiliated with Genentech. The author has no financial interests to declare..
  11. Dewakar Sangaraju

    Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, United States
    Competing interests
    Dewakar Sangaraju, is affiliated with Genentech. The author has no financial interests to declare..
  12. Heinrich Jasper

    Regenerative Medicine, Genentech, South San Francisco, United States
    For correspondence
    jasperh@gene.com
    Competing interests
    Heinrich Jasper, is affiliated with Genentech. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6014-4343

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.

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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  1. Nadja S Katheder
  2. Kristen C Browder
  3. Diana Chang
  4. Ann De Maziere
  5. Pekka Kujala
  6. Suzanne van Dijk
  7. Judith Klumperman
  8. Tzu-Chiao Lu
  9. Hongjie Li
  10. Zijuan Lai
  11. Dewakar Sangaraju
  12. Heinrich Jasper
(2023)
Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity
eLife 12:e86381.
https://doi.org/10.7554/eLife.86381

Share this article

https://doi.org/10.7554/eLife.86381

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