(The) roles of mTORC1 pathway in retinal progenitor cells

Abstract

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 regulation of growth and development of mouse retina. We found that in mTORC1-hyperactive Tuberous sclerosis complex 1 (Tsc1)-deficient mouse retina, retinal progenitor cells (RPCs) undergo accelerated cell cycle progression and precocious neurogenesis. The evidences showed that mTORC1 activation facilitates both the synthesis and degradation of cyclin proteins to regulate mitotic cell cycle progression of RPCs and consequently the retinal neurogenesis. We showed that mTORC1 induces the expression of immunoproteasome component Psmb9 via signal transducer and activator of transcription 1 (Stat1) in the RPCs, and concomitant loss of Psmb9 decelerates cell cycle progression of RPCs in Tsc1-deficient mouse and normalizes retinal developmental schedule. Collectively, our results establish a developmental role for PI3K-Akt-mTORC1 pathway, showing that it promotes neural development by coupling synthesis and degradation of cell cycle regulator proteins in the progenitor cells through activation of protein turnover via a mechanism involving the immunoproteasome.