mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
- Korea Advanced Institute of Science and Technology, Republic of Korea
- University of Ulsan College of Medicine, Republic of Korea
- Fukushima Medical University, Japan
- Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic
- 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
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.
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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
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