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.
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Acknowledgements
We would like to thank J. Johnson and B. Cregg for a critical reading of the manuscript and D. Rowitch for communicating their unpublished results. We thank W. Walker, A. Iavarone, Y. Yokota, K. Kim, R. Miskimins and J. Suh for Id2 and Id4, Mbp promoter reporters, and β-catenin and TCF expression vectors, and X. Xu for technical assistance. This study was funded by grants from the US National Multiple Sclerosis Society (RG3978 and PP0144) and the US National Institutes of Health (NS050389 to Q.R.L.). Q.R.L. is a Harry Weaver Neuroscience Scholar and a Basil O'Connor Scholar.
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Q.R.L. designed the study, analyzed the data and coordinated the project. F.Y., Y.C., T.N.H., X.-H.Z. and T.H. performed the morphological analysis and biochemical assays. H.B. provided resources. M.M.T. provided the Ctnnb1ex3 mice. J.H.E. and H.C. provided TCF7l2 mutant mice. J.H. provided HCN cell culture. R.L.M., R.B.-D. and E.N.O. provided Hdac1loxP/loxP and Hdac2loxP/loxP mice and contributed conceptually to the project. The manuscript was written by Q.R.L., edited by R.B.D. and E.N.O., and commented on by all authors.
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Ye, F., Chen, Y., Hoang, T. et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interaction. Nat Neurosci 12, 829–838 (2009). https://doi.org/10.1038/nn.2333
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DOI: https://doi.org/10.1038/nn.2333
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