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

Feng Ye, Ying Chen, Thaonguyen Hoang, Rusty L. Montgomery, Xian Hui Zhao, Hong Bu, Tom Hu, Makoto M. Taketo, Johan H. Van Es, Hans Clevers, Jenny Hsieh, Rhonda S Bassel-Duby, Eric N Olson, Q. Richard Lu

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Abstract

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 Β-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 Β-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 Β-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.

Original languageEnglish (US)
Pages (from-to)829-838
Number of pages10
JournalNature neuroscience
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2009

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ye, F., Chen, Y., Hoang, T., Montgomery, R. L., Zhao, X. H., Bu, H., Hu, T., Taketo, M. M., Van Es, J. H., Clevers, H., Hsieh, J., Bassel-Duby, R. S., Olson, E. N., & Lu, Q. R. (2009). HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the Β-catenin-TCF interaction. Nature neuroscience, 12(7), 829-838. https://doi.org/10.1038/nn.2333