Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Abstract

Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here we report that Trpv6, a cation channel responsible for epithelial Ca2+ absorption, functions as a key regulator of cellular quiescence. Genetic deletion and pharmacological blockade of Trpv6 promoted zebrafish epithelial cells to exit from quiescence and re-enter the cell cycle. Reintroducing Trpv6, but not its channel dead mutant, restored the quiescent state. Ca2+ imaging showed that Trpv6 is constitutively open in vivo. Mechanistically, Trpv6-mediated Ca2+ influx maintained the quiescent state by suppressing insulin-like growth factor (IGF)-mediated Akt-Tor and Erk signaling. In zebrafish epithelia and human colon carcinoma cells, Trpv6/TRPV6 elevated intracellular Ca2+ levels and activated PP2A, which down-regulated IGF signaling and promoted the quiescent state. Our findings suggest that Trpv6 mediates constitutive Ca2+ influx into epithelial cells to continuously suppress growth factor signaling and maintain the quiescent state.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yi Xin

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Allison Malick

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Meiqin Hu

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chengdong Liu

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Heya Batah

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Haoxing Xu

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3561-4654
  7. Cunming Duan

    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    For correspondence
    cduan@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6794-2762

Funding

National Science Foundation (IOS-1557850)

  • Cunming Duan

National Science Foundation (IOS-1755262)

  • Cunming Duan

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

Reviewing Editor

  1. Rosemary O’Connor

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were conducted in accordance with the protocol approved by the University of Michigan Institutional Committee on the Use and Care of Animals (Protocol # PRO00008801).

Version history

  1. Received: April 26, 2019
  2. Accepted: September 13, 2019
  3. Accepted Manuscript published: September 17, 2019 (version 1)
  4. Version of Record published: September 27, 2019 (version 2)
  5. Version of Record updated: June 25, 2020 (version 3)

Copyright

© 2019, Xin 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. Yi Xin
  2. Allison Malick
  3. Meiqin Hu
  4. Chengdong Liu
  5. Heya Batah
  6. Haoxing Xu
  7. Cunming Duan
(2019)
Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6
eLife 8:e48003.
https://doi.org/10.7554/eLife.48003

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https://doi.org/10.7554/eLife.48003

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