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

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

Authors

  • Ye F
  • Chen Y
  • Hoang T
  • Montgomery RL
  • Zhao XH
  • Bu H
  • Hu T
  • Taketo MM
  • van Es JH
  • Clevers H
  • Hsieh J
  • Bassel-Duby R
  • Olson EN
  • Lu QR

Journal

Nature neuroscience

Publication Data

July 25, 2009

Associated Grants

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

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