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

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Cite this article as: eLife 2019;8:e48003 doi: 10.7554/eLife.48003

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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.

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Author details

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.
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.
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.
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.
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.
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.

"This ORCID iD identifies the author of this article:" 0000-0003-3561-4654
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.

"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.

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).

Reviewing Editor

Rosemary O’Connor

Publication history

Received: April 26, 2019
Accepted: September 13, 2019
Accepted Manuscript published: September 17, 2019 (version 1)
Version of Record published: September 27, 2019 (version 2)

Copyright

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.