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HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction.

Nature neuroscience | Jul 25, 2009

Oligodendrocyte development is regulated by the interaction of repressors and activators in a complex transcriptional network. We found that two histone-modifying enzymes, HDAC1 and HDAC2, were required for oligodendrocyte formation. Genetic deletion of both Hdac1 and Hdac2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of beta-catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified the oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of beta-catenin for regulating oligodendrocyte differentiation. Targeted disruption of Tcf7l2 in mice led to severe defects in oligodendrocyte maturation, whereas expression of its dominant-repressive form promoted precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with beta-catenin for TCF7L2 interaction to regulate downstream genes involved in oligodendrocyte differentiation. Thus, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.

Pubmed ID: 19503085 RIS Download

Mesh terms: Animals | Astrocytes | Brain | Cell Differentiation | Cells, Cultured | Chick Embryo | Female | Histone Deacetylase 1 | Histone Deacetylase 2 | Histone Deacetylases | Mice | Mice, Transgenic | Motor Neurons | Mutation | Oligodendroglia | Rats | Rats, Inbred F344 | Repressor Proteins | Signal Transduction | Spinal Cord | TCF Transcription Factors | Transcription Factor 7-Like 2 Protein | Wnt Proteins | beta Catenin

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS050389
  • Agency: NINDS NIH HHS, Id: R01 NS050389-04
  • Agency: NINDS NIH HHS, Id: NS050389

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