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-alpha (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.

Department of Biochemistry College of Life Science and Biotechnology Yonsei University Yonsei Republic of Korea

Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon Republic of Korea

Department of Convergence Medicine Asan Medical Center University of Ulsan College of Medicine Seoul Republic of Korea

Department of Obesity and Internal Inflammation; Bioregulation and Pharmacological Medicine Fukushima Medical University Fukushima Japan

Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

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