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
Nature
Date: Oct. 31, 2002
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