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 Bassel-Duby, Eric N. Olson, Q. Richard Lu

Research output: Contribution to journalArticlepeer-review

485 Citations (Scopus)

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
Pages (from-to)829-838
Number of pages10
JournalNature Neuroscience
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 2009
Externally publishedYes

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