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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Astrocytes / cytology*
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Astrocytes / drug effects
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Astrocytes / enzymology
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Astrocytes / metabolism
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Cell Differentiation* / drug effects
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Cell Division / drug effects
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Cell Line
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Cell Nucleus / metabolism
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Chromatin / metabolism
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Ciliary Neurotrophic Factor / pharmacology
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Cytoplasm / metabolism
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Enzyme Activation
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Fibroblast Growth Factor 2 / pharmacology
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Humans
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Mice
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Neurons / cytology*
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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Nuclear Proteins / metabolism*
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Nuclear Receptor Co-Repressor 1
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation / drug effects
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Protein Phosphatase 1
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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Repressor Proteins / metabolism*
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Stem Cells / cytology*
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Stem Cells / drug effects
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Stem Cells / enzymology
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Stem Cells / metabolism
Substances
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Chromatin
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Ciliary Neurotrophic Factor
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NCOR1 protein, human
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Ncor1 protein, mouse
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Proto-Oncogene Proteins
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Repressor Proteins
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Fibroblast Growth Factor 2
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoprotein Phosphatases
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Protein Phosphatase 1