Article abstract
Nature Neuroscience 12, 829 - 838 (2009)
Published online: 7 June 2009 | doi:10.1038/nn.2333
HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the 
-catenin–TCF interaction
Feng Ye1,2, Ying Chen1, ThaoNguyen Hoang1, Rusty L Montgomery3, Xian-hui Zhao1, Hong Bu2, Tom Hu1, Makoto M Taketo4, Johan H van Es5, Hans Clevers5, Jenny Hsieh3, Rhonda Bassel-Duby3, Eric N Olson3 & Q Richard Lu1,3,6
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 
-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 -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 -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.
- Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, China.
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Hubrecht Institute, Utrecht, The Netherlands.
- West China Second University Hospital, Sichuan University, China.
Correspondence to: Q Richard Lu1,3,6 e-mail: qrichard.lu@utsouthwestern.edu
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