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N-CoR controls differentiation of neural stem cells into astrocytes.

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.

Pubmed ID: 12410313

Authors

  • Hermanson O
  • Jepsen K
  • Rosenfeld MG

Journal

Nature

Publication Data

October 31, 2002

Associated Grants

None

Mesh Terms

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