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.
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
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
Nature
Date: Oct. 31, 2002
PubMed ID: 12410313
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