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N-CoR controls differentiation of neural stem cells into astrocytes

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)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).

References

  1. Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001)

    ADS  CAS  Article  Google Scholar 

  2. Ghosh, A. & Greenberg, M. E. Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron 15, 89–103 (1995)

    CAS  Article  Google Scholar 

  3. Johe, K. K., Hazel, T. G., Muller, T., Dugich-Djordjevic, M. M. & McKay, R. D. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 10, 3129–3140 (1996)

    CAS  Article  Google Scholar 

  4. Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999)

    CAS  Article  Google Scholar 

  5. Temple, S. & Alvarez-Buylla, A. Stem cells in the adult mammalian central nervous system. Curr. Opin. Neurobiol. 9, 135–141 (1999)

    CAS  Article  Google Scholar 

  6. Hörlein, A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995)

    ADS  Article  Google Scholar 

  7. Kao, H. Y. et al. A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 12, 2269–2277 (1998)

    CAS  Article  Google Scholar 

  8. Frisén, J. & Lendahl, U. Oh no, Notch again! Bioessays 23, 3–7 (2001)

    Article  Google Scholar 

  9. Faux, C. H., Turnley, A. M., Epa, R., Cappai, R. & Bartlett, P. F. Interactions between fibroblast growth factors and Notch regulate neuronal differentiation. J. Neurosci. 21, 5587–5596 (2001)

    CAS  Article  Google Scholar 

  10. Hitoshi, S. et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 16, 846–858 (2002)

    CAS  Article  Google Scholar 

  11. Jepsen, K. et al. Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102, 753–763 (2000)

    CAS  Article  Google Scholar 

  12. Raballo, R. et al. Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex. J. Neurosci. 20, 5012–5023 (2000)

    CAS  Article  Google Scholar 

  13. Rao, M. S., Noble, M. & Mayer-Proschel, M. A tripotential glial precursor cell is present in the developing spinal cord. Proc. Natl Acad. Sci. USA 95, 3996–4001 (1998)

    ADS  CAS  Article  Google Scholar 

  14. Choi, B. H. Prenatal gliogenesis in the developing cerebrum of the mouse. Glia 1, 308–316 (1988)

    CAS  Article  Google Scholar 

  15. Yasui, Y. et al. Roles of Rho-associated kinase in cytokinesis; mutations in Rho-associated kinase phosphorylation sites impair cytokinetic segregation of glial filaments. J. Cell Biol. 143, 1249–1258 (1998)

    CAS  Article  Google Scholar 

  16. Perissi, V. et al. Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 13, 3198–3208 (1999)

    CAS  Article  Google Scholar 

  17. Besnard, F. et al. Multiple interacting sites regulate astrocyte-specific transcription of the human gene for glial fibrillary acidic protein. J. Biol. Chem. 266, 18877–18883 (1991)

    CAS  PubMed  Google Scholar 

  18. Kaneko, R., Hagiwara, N., Leader, K. & Sueoka, N. Glial-specific cAMP response of the glial fibrillary acidic protein gene cell lines. Proc. Natl Acad. Sci. USA 91, 4529–4533 (1994)

    ADS  CAS  Article  Google Scholar 

  19. Kahn, M. A. et al. Ciliary neurotrophic factor activates JAK/Stat signal transduction cascade and induces transcriptional expression of glial fibrillary acidic protein in glial cells. J. Neurochem. 68, 1413–1423 (1997)

    CAS  Article  Google Scholar 

  20. Bellacosa, A., Testa, J. R., Staal, S. P. & Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254, 274–277 (1991)

    ADS  CAS  Article  Google Scholar 

  21. Morrison, S. J. Pten-uating neural growth. Nature Med. 8, 16–18 (2002)

    CAS  Article  Google Scholar 

  22. Rhee, Y., Gurel, F., Gafni, Y., Dingwall, C. & Citovsky, V. A genetic system for detection of protein nuclear import and export. Nature Biotechnol. 18, 433–437 (2000)

    CAS  Article  Google Scholar 

  23. Yaffe, M. B. et al. A motif-based profile scanning approach for genome-wide prediction of signaling pathways. Nature Biotechnol. 19, 348–353 (2001)

    CAS  Article  Google Scholar 

  24. Egloff, M. P. et al. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 16, 1876–1887 (1997)

    CAS  Article  Google Scholar 

  25. Aggen, J. B., Nairn, A. C. & Chamberlin, R. Regulation of protein phosphatase-1. Chem. Biol. 7, R13–R23 (2000)

    CAS  Article  Google Scholar 

  26. Molne, M. et al. Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J. Neurosci. Res. 59, 301–311 (2000)

    ADS  CAS  Article  Google Scholar 

  27. Sauvageot, C. M. & Stiles, C. D. Molecular mechanisms controlling cortical gliogenesis. Curr. Opin. Neurobiol. 12, 244–249 (2002)

    CAS  Article  Google Scholar 

  28. Braunstein, M., Rose, A. B., Holmes, S. G., Allis, C. D. & Broach, J. R. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592–604 (1993)

    CAS  Article  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/nature01156

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