RESUMEN
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.
Asunto(s)
Células Ependimogliales/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Retina/patología , Células Madre/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Mitosis , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
The numbers and types of cells constituting vertebrate neural tissues are determined by cellular mechanisms that couple neurogenesis to the proliferation of neural progenitor cells. Here we identified a role of mammalian target of rapamycin complex 1 (mTORC1) in the development of neural tissue, showing that it accelerates progenitor cell cycle progression and neurogenesis in mTORC1-hyperactive tuberous sclerosis complex 1 (Tsc1)-deficient mouse retina. We also show that concomitant loss of immunoproteasome subunit Psmb9, which is induced by Stat1 (signal transducer and activator of transcription factor 1), decelerates cell cycle progression of Tsc1-deficient mouse retinal progenitor cells and normalizes retinal developmental schedule. Collectively, our results establish a developmental role for mTORC1, showing that it promotes neural development through activation of protein turnover via a mechanism involving the immunoproteasome.
Asunto(s)
Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neurogénesis/fisiología , Retina/crecimiento & desarrollo , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo , Animales , Ciclo Celular/fisiología , División Celular/fisiología , Cisteína Endopeptidasas/metabolismo , Embrión de Mamíferos , Femenino , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Retina/citología , Retina/metabolismo , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/fisiología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.