Chloride channels regulate differentiation and barrier functions of the mammalian airway

  1. Mu He  Is a corresponding author
  2. Bing Wu
  3. Wenlei Ye
  4. Daniel D Le
  5. Adriane W Sinclair
  6. Valeria Padovano
  7. Yuzhang Chen
  8. Ke-Xin Li
  9. Rene Sit
  10. Michelle Tan
  11. Michael J Caplan
  12. Norma Neff
  13. Yuh Nung Jan
  14. Spyros Darmanis  Is a corresponding author
  15. Lily Yeh Jan  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Chan Zuckerberg Biohub, United States
  3. Yale University School of Medicine, United States

Abstract

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/- mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.

Data availability

Sequencing reads and processed data in the format of gene-cell count tables are available from the Sequence Read Archive (SRA) (​SRA accession​: PRJNA548516).

The following data sets were generated

Article and author information

Author details

  1. Mu He

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    mu.he@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Bing Wu

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Wenlei Ye

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4694-1493
  4. Daniel D Le

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Adriane W Sinclair

    Division of Pediatric Urology, Department of Urology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Valeria Padovano

    Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0142-3385
  7. Yuzhang Chen

    Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ke-Xin Li

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3879-294X
  9. Rene Sit

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Michelle Tan

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael J Caplan

    Department of Cellular and Molecular Physiology; Department of Cell Biology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Norma Neff

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yuh Nung Jan

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1367-6299
  14. Spyros Darmanis

    Chan Zuckerberg Biohub, San Francisco, United States
    For correspondence
    spyros.darmanis@czbiohub.org
    Competing interests
    The authors declare that no competing interests exist.
  15. Lily Yeh Jan

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Lily.Jan@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3938-8498

Funding

National Institute of Neurological Disorders and Stroke (RO1 NS069229)

  • Lily Yeh Jan

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD089639)

  • Mu He

Howard Hughes Medical Institute

  • Yuh Nung Jan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, He 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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https://doi.org/10.7554/eLife.53085

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