mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

  1. Soyeon Lim
  2. You-Joung Kim
  3. Sooyeon Park
  4. Ji-heon Choi
  5. Younghoon Sung
  6. Katsuhiko Nishimori
  7. Zybmek Kozmik
  8. Han-Woong Lee
  9. Jin Woo Kim  Is a corresponding author
  1. Korea Advanced Institute of Science and Technology, Republic of Korea
  2. University of Ulsan College of Medicine, Republic of Korea
  3. Fukushima Medical University, Japan
  4. Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic
  5. Yonsei University, Republic of Korea

Abstract

Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 and 2.

Article and author information

Author details

  1. Soyeon Lim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. You-Joung Kim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Sooyeon Park

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Ji-heon Choi

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9204-1755
  5. Younghoon Sung

    Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Katsuhiko Nishimori

    Obesity and Internal Inflammation; Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Zybmek Kozmik

    Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  8. Han-Woong Lee

    Biochemistry, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9515-3605
  9. Jin Woo Kim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    For correspondence
    jinwookim@kaist.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0767-1918

Funding

National Research Foundation of Korea (2017R1A2B3002862)

  • Jin Woo Kim

National Research Foundation of Korea (2018R1A5A1024261)

  • Jin Woo Kim

Samsung Science and Technology Foundation (SSTF-BA1802-10)

  • Jin Woo Kim

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

Reviewing Editor

  1. Paola Bovolenta, CSIC-UAM, Spain

Ethics

Animal experimentation: Experiments using the mice were carried out according to the guidance of Institutional Animal Care and Use Committee (IACUC) of KAIST (KA-2014-20).

Version history

  1. Received: May 5, 2021
  2. Accepted: October 17, 2021
  3. Accepted Manuscript published: October 22, 2021 (version 1)
  4. Version of Record published: November 9, 2021 (version 2)

Copyright

© 2021, Lim 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. Soyeon Lim
  2. You-Joung Kim
  3. Sooyeon Park
  4. Ji-heon Choi
  5. Younghoon Sung
  6. Katsuhiko Nishimori
  7. Zybmek Kozmik
  8. Han-Woong Lee
  9. Jin Woo Kim
(2021)
mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
eLife 10:e70079.
https://doi.org/10.7554/eLife.70079

Share this article

https://doi.org/10.7554/eLife.70079

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