PT - JOURNAL ARTICLE AU - Sheng Zhang AU - Yan Wang AU - Xiaoqing Zhu AU - Lanying Song AU - Edric Ma AU - Jennifer McDonough AU - Hui Fu AU - Franca Cambi AU - Judith Grinspan AU - Fuzheng Guo TI - The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling AID - 10.1101/2020.09.16.300624 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.09.16.300624 4099 - http://biorxiv.org/content/early/2020/09/16/2020.09.16.300624.short 4100 - http://biorxiv.org/content/early/2020/09/16/2020.09.16.300624.full AB - Promoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo. Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested oligodendrocyte differentiation elicited by TCF7l2 disruption in vivo. Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.Competing Interest StatementThe authors have declared no competing interest.