N-CoR controls differentiation of neural stem cells into astrocytes

Nature. 2002 Oct 31;419(6910):934-9. doi: 10.1038/nature01156. Epub 2002 Oct 16.

Abstract

Understanding the gene programmes that regulate maintenance and differentiation of neural stem cells is a central question in stem cell biology. Virtually all neural stem cells maintain an undifferentiated state and the capacity to self-renew in response to fibroblast growth factor-2 (FGF2). Here we report that a repressor of transcription, the nuclear receptor co-repressor (N-CoR), is a principal regulator in neural stem cells, as FGF2-treated embryonic cortical progenitors from N-CoR gene-disrupted mice display impaired self-renewal and spontaneous differentiation into astroglia-like cells. Stimulation of wild-type neural stem cells with ciliary neurotrophic factor (CNTF), a differentiation-inducing cytokine, results in phosphatidylinositol-3-OH kinase/Akt1 kinase-dependent phosphorylation of N-CoR, and causes a temporally correlated redistribution of N-CoR to the cytoplasm. We find that this is a critical strategy for cytokine-induced astroglia differentiation and lineage-characteristic gene expression. Recruitment of protein phosphatase-1 to a specific binding site on N-CoR exerts a reciprocal effect on the cellular localization of N-CoR. We propose that repression by N-CoR, modulated by opposing enzymatic activities, is a critical mechanism in neural stem cells that underlies the inhibition of glial differentiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Astrocytes / drug effects
  • Astrocytes / enzymology
  • Astrocytes / metabolism
  • Cell Differentiation* / drug effects
  • Cell Division / drug effects
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromatin / metabolism
  • Ciliary Neurotrophic Factor / pharmacology
  • Cytoplasm / metabolism
  • Enzyme Activation
  • Fibroblast Growth Factor 2 / pharmacology
  • Humans
  • Mice
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / metabolism
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Co-Repressor 1
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Protein Phosphatase 1
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Repressor Proteins / metabolism*
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / enzymology
  • Stem Cells / metabolism

Substances

  • Chromatin
  • Ciliary Neurotrophic Factor
  • NCOR1 protein, human
  • Ncor1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Fibroblast Growth Factor 2
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1