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.

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).

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.

Metrics

  • 1,734
    views
  • 210
    downloads
  • 7
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Hope M Healey, Hayden B Penn ... William A Cresko
    Research Article

    Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provided the opportunity for detailed genetic analyses. We created a single-cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined the spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting that derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how the novelties of these fish evolved.

    1. Developmental Biology
    2. Genetics and Genomics
    Mehul Vora, Jonathan Dietz ... Cathy Savage-Dunn
    Research Article

    Smads and their transcription factor partners mediate the transcriptional responses of target cells to secreted ligands of the transforming growth factor-β (TGF-β) family, including those of the conserved bone morphogenetic protein (BMP) family, yet only a small number of direct target genes have been well characterized. In C. elegans, the BMP2/4 ortholog DBL-1 regulates multiple biological functions, including body size, via a canonical receptor-Smad signaling cascade. Here, we identify functional binding sites for SMA-3/Smad and its transcriptional partner SMA-9/Schnurri based on ChIP-seq peaks (identified by modEncode) and expression differences of nearby genes identified from RNA-seq analysis of corresponding mutants. We found that SMA-3 and SMA-9 have both overlapping and unique target genes. At a genome-wide scale, SMA-3/Smad acts as a transcriptional activator, whereas SMA-9/Schnurri direct targets include both activated and repressed genes. Mutations in sma-9 partially suppress the small body size phenotype of sma-3, suggesting some level of antagonism between these factors and challenging the prevailing model for Schnurri function. Functional analysis of target genes revealed a novel role in body size for genes involved in one-carbon metabolism and in the endoplasmic reticulum (ER) secretory pathway, including the disulfide reductase dpy-11. Our findings indicate that Smads and SMA-9/Schnurri have previously unappreciated complex genetic and genomic regulatory interactions that in turn regulate the secretion of extracellular components like collagen into the cuticle to mediate body size regulation.