Nuclear receptor NR5A2 controls neural stem cell fate decisions during development

Nat Commun. 2016 Jul 22;7:12230. doi: 10.1038/ncomms12230.

Abstract

The enormous complexity of mammalian central nervous system (CNS) is generated by highly synchronized actions of diverse factors and signalling molecules in neural stem/progenitor cells (NSCs). However, the molecular mechanisms that integrate extrinsic and intrinsic signals to control proliferation versus differentiation decisions of NSCs are not well-understood. Here we identify nuclear receptor NR5A2 as a central node in these regulatory networks and key player in neural development. Overexpression and loss-of-function experiments in primary NSCs and mouse embryos suggest that NR5A2 synchronizes cell-cycle exit with induction of neurogenesis and inhibition of astrogliogenesis by direct regulatory effects on Ink4/Arf locus, Prox1, a downstream target of proneural genes, as well as Notch1 and JAK/STAT signalling pathways. Upstream of NR5a2, proneural genes, as well as Notch1 and JAK/STAT pathways control NR5a2 endogenous expression. Collectively, these observations render NR5A2 a critical regulator of neural development and target gene for NSC-based treatments of CNS-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Cell Differentiation*
  • Cell Proliferation
  • Central Nervous System / embryology*
  • Cyclin-Dependent Kinase Inhibitor Proteins / metabolism
  • Homeodomain Proteins / metabolism
  • MAP Kinase Signaling System
  • Mice, Knockout
  • Neural Stem Cells / physiology*
  • Neurogenesis*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • STAT Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Homeodomain Proteins
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • STAT Transcription Factors
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • ADP-Ribosylation Factors