mTORC1 accelerates retinal development via the immunoproteasome

Nat Commun. 2018 Jun 27;9(1):2502. doi: 10.1038/s41467-018-04774-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cell Division / physiology
  • Cysteine Endopeptidases / metabolism
  • Embryo, Mammalian
  • Female
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Knockout
  • Neural Stem Cells / metabolism
  • Neurogenesis / physiology*
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • Retina / cytology
  • Retina / growth & development*
  • Retina / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / physiology
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tuberous Sclerosis Complex 1 Protein / metabolism*

Substances

  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • LMP-2 protein
  • Mechanistic Target of Rapamycin Complex 1
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex