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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)1,2,3,4,5. 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 cytokine3, 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.

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Figure 1: N-CoR is a regulator of neural stem cell state.
Figure 2: The subcellular localization of N-CoR is altered by CNTF, and nuclear N-CoR represses CNTF-mediated astroglia differentiation and GFAP expression.
Figure 3: Akt1 kinase activation in neural stem cells is required for CNTF-mediated astroglia differentiation, GFAP expression, and re-localization of N-CoR.
Figure 4: The subcellular localization of N-CoR is regulated through direct targeting by Akt1 kinase and protein phosphatase-1 (PP-1).


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We are grateful to L. van Grunsven and R. McKay for their help in neural stem cell biology, and for providing advice throughout this study. Constructs and reagents were provided by D. Altomare, J. Testa, E. Lamar, C. Kintner, J. De Vellis, B. Andersen, T. Sugihara, D. Rose, and the Campagnoni Laboratory. We are also grateful to S. McMullen for microscopy assistance; C. Nelson and A. Krones for various cell culture assistance; H. Taylor for animal care; P. Myer for artwork; M. Fisher for assistance with the manuscript; V. Perissi for numerous reagents, discussions, and advice on ChIP; and members of the Rosenfeld laboratory for comments, discussions and various reagents, in particular L. Erkman, A. Gleiberman, V. Kumar, R. McEvilly and D. Solum. M.G.R. is an investigator with the Howard Hughes Medical Institute. O.H. was partially funded by the Swedish Brain Foundation. This work was funded by a grant from NIH.

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Correspondence to Michael G. Rosenfeld.

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Hermanson, O., Jepsen, K. & Rosenfeld, M. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934–939 (2002).

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