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 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.
Highlights
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
The latter effects of mammalian target of rapamycin complex 1 (mTORC1) are mediated by upregulation of proteasome subunits, especially the immunoproteasome subunit Psmb[9] in the retinal progenitor cells (RPCs)
The immunoproteasome subunits were elevated in the Tsc1flox/flox;Emx1-Cre mouse embryonic brain and were decreased in the rapamycin-treated adult mouse spleen (Supplementary Fig. 11), suggesting that induction of the immunoproteasome is a common outcome of mTORC1 activation
Summary
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. 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. Decisions of RPCs to maintain their fate or exit cell cycle to differentiate to retinal neurons are combined outputs of internal determinants and external signals. Similar autonomous neurogenic acceleration has been observed in Pten-deficient mouse retinas, in which hyperproliferating RPCs produce all types of retinal neurons in advance of their regular schedule[14]. In both cases, Akt-hyperactive RPCs do not expand themselves, but they produce retinal neurons more rapidly than neighboring WT RPCs
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