HDAC1 and HDAC2 Regulate Oligodendrocyte Differentiation By Disrupting β-Catenin-TCF Interaction

Oligodendrocyte development is regulated by the interplay of repressors and activators in a complex transcriptional network. Here we report that two histone-modifying enzymes, HDAC1 and HDAC2, are 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 an oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of β-catenin for regulating oligodendrocyte differentiation. Targeted disruption of TCF7L2 in mice leads to severe defects in oligodendrocyte maturation, while expression of its dominant repressive form promotes 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. Hence, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.