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-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.
Highlights
Neural progenitor cells (NPCs) divide repeatedly during development to generate the cells of vertebrate neural tissues (Homem et al, 2015; Obernier and Alvarez-Buylla, 2019)
Degeneration of Müller glia (MG) derived from tuberous sclerosis complex 1 (Tsc1)-deficient ciliary margin (CM) Retinal progenitor cells (RPCs) mechanistic target of rapamycin complex 1 (mTORC1) activity, which leads to the phosphorylation of ribosomal protein S6 via the activation of S6 kinase 1 (S6K1), was detectable in developing mouse retina but was absent in the neighboring retinal pigment epithelium (RPE) and CM (Figure 1 – figure supplement 1). it is unknown why mTORC1 activity is diversified in the optic neuroepithelial continuum of the retina-CM-RPE, which were shown to exhibit differential proliferation rates (Moon et al, 2018)
The deletion of Tsc2 from the RPE and CM of Tsc2fl/fl;Tyrp1-Cre mice did not cause ciliary body (CB)/iris malformations, the mice shared the retinal phenotypes of Tsc1fl/fl;Tyrp1-Cre mice (Figure 1 – figure supplement 4)
Summary
Neural progenitor cells (NPCs) divide repeatedly during development to generate the cells of vertebrate neural tissues (Homem et al, 2015; Obernier and Alvarez-Buylla, 2019). NPCs are present for a limited period before entering a final cell division for the differentiation to neurons and glia. NPCs are not seen in the majority of adult neural tissues, 44 except for sub-brain areas that exhibit continued neurogenesis. It has been identified that the mitotic characteristics of NPCs change continually in the development of neural tissues. Most NPCs divide symmetrically to expand themselves during early development; thereafter, the asymmetrically dividing NPCs increase to preserve the NPC population while actively generating the various types of neurons and glia
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