Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Young Hoon Sung
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Yonsei, Republic of Korea; Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Katsuhiko Nishimori
Department of Obesity and Internal Inflammation; Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
Zbynek Kozmik
Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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.
