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.
Hermanson
Ola
O
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA.
Jepsen
Kristen
K
Rosenfeld
Michael G
MG
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D002843:Chromatin; D020934:Ciliary Neurotrophic Factor; D016222:Fibroblast Growth Factor 2; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; C494918:AKT1 protein, human