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.

• Klíčová slova
• mTORC1, Hif1a, clonal expansion, developmental biology, glycolysis, hypoxia-induced factor 1-alpha, mechanistic target of rapamycin complex 1, mitotic division limit, mouse, retinal progenitor cell,
• MeSH
• ependymální buňky patologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• hamartin genetika   metabolismus   MeSH
• kmenové buňky patologie   MeSH
• mitóza MeSH
• mTORC1 genetika   metabolismus   MeSH
• myši MeSH
• retina patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• hamartin MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• mTORC1 MeSH
• Tsc1 protein, mouse MeSH Prohlížeč

Genome duplication leads to an emergence of gene paralogs that are essentially free to undergo the process of neofunctionalization, subfunctionalization or degeneration (gene loss). Onecut1 (Oc1) and Onecut2 (Oc2) transcription factors, encoded by paralogous genes in mammals, are expressed in precursors of horizontal cells (HCs), retinal ganglion cells and cone photoreceptors. Previous studies have shown that ablation of either Oc1 or Oc2 gene in the mouse retina results in a decreased number of HCs, while simultaneous deletion of Oc1 and Oc2 leads to a complete loss of HCs. Here we study the genetic redundancy between Oc1 and Oc2 paralogs and focus on how the dose of Onecut transcription factors influences abundance of individual retinal cell types and overall retina physiology. Our data show that reducing the number of functional Oc alleles in the developing retina leads to a gradual decrease in the number of HCs, progressive thinning of the outer plexiform layer and diminished electrophysiology responses. Taken together, these observations indicate that in the context of HC population, the alleles of Oc1/Oc2 paralogous genes are mutually interchangeable, function additively to support proper retinal function and their molecular evolution does not follow one of the typical routes after gene duplication.

• MeSH
• alely MeSH
• amakrinní buňky metabolismus   patologie   MeSH
• bipolární buňky sítnice metabolismus   patologie   MeSH
• čípky retiny metabolismus   patologie   MeSH
• ependymální buňky metabolismus   patologie   MeSH
• genetické lokusy MeSH
• genotyp MeSH
• hepatocytární jaderný faktor 6 genetika   metabolismus   MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• oči růst a vývoj   patologie   MeSH
• retina cytologie   patologie   fyziologie   MeSH
• retinální gangliové buňky cytologie   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hepatocytární jaderný faktor 6 MeSH
• homeodoménové proteiny MeSH
• Onecut1 protein, mouse MeSH Prohlížeč
• ONECUT2 protein, mouse MeSH Prohlížeč
• transkripční faktory MeSH