Investigation of the role of mTORC1 pathway in retinal progenitor cells derived from ciliary margin

Abstract

The cells comprising vertebrate retinas are derived from retinal progenitor cells (RPCs). The activation of mechanistic target of rapamycin complex 1 (mTORC1) was shown to enhance cell cycle progression of RPC, and thereby accelerate retinal development. In this study, I found that mTORC1 activation by deletion of tuberous sclerosis complex 1 (Tsc1) in ciliary RPC clones, promotes RPC proliferation, leading to hyperexpansion of Tsc1-deficient RPC clones, and consequently causes retinal degeneration due to a loss of Müller glia (MG). I also found that retinal cells derived from the Tsc1-deficient RPCs are mitotically older than neighboring wild-type cells and express senescence markers. The mTORC1-induced mitotic aging, senescence, and retinal degeneration was suppressed by concomitant deletion of hypoxia-induced factor 1-alpha (Hif1a), which induces glycolytic gene expression to supply the energy necessary for RPC hyperproliferation. In conclusion, these results suggest that rapidly dividing RPCs exhaust their mitotic capacity faster than adjacent RPCs, thus it produces retinal cells that exceed mitotic division limits and prematurely degenerate.