@article{9441bbd5658b49c3a1e98117299dcd31,
title = "The wnt effector tcf7l2 promotes oligodendroglial differentiation by repressing autocrine bmp4-mediated signaling",
abstract = "Promoting oligodendrocyte (OL) differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector transcription factor 7-like 2 (TCF7l2) was upregulated in MS lesions and had been proposed to inhibit OL 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 (BMP)4-mediated signaling. Disrupting TCF7l2 in mice of both sexes 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 OL differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested OL 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.",
keywords = "Bmp4 repression, Canonical wnt/b-catenin, Myelination, Oligodendrocyte differentiation, Tcf7l2/tcf4, Wnt effector",
author = "Sheng Zhang and Yan Wang and Xiaoqing Zhu and Lanying Song and Xinhua Zhan and Edric Ma and Jennifer McDonough and Hui Fu and Franca Cambi and Judith Grinspan and Fuzheng Guo",
note = "Funding Information: Received Sep. 12, 2020; revised Dec. 2, 2020; accepted Jan. 1, 2021. pS.Z. and Y.W. are co-first authors. Author contributions: J.G. and F.G. designed research; S.Z., Y.W., X.Zhu, L.S., and E.M. performed research; X.Zha., E.M., H.F., J.M., F.C., J.G., and F.G. contributed unpublished reagents/analytic tools; S.Z., Y.W., X.Zhu, L.S., H.F., F.C., J.G., and F.G. analyzed data; S.Z., Y.W., J.G., and F.G. wrote the paper. This work was funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke Grants R21NS109790 and R01NS094559 and by Shriners Hospitals for Children Grants 85107-NCA-19, 84553-NCA-18, and 84307-NCAL. We thank Dr. Andreas Hecht (University of Freiburg, Germany) for providing TCF7l2-E2, M1, and S2 expression vectors and Dr. Gino Cortopassi (University of California, Davis) for providing U87 cells. The authors declare no competing financial interests. Correspondence should be addressed to Fuzheng Guo at fzguo@ucdavis.edu. https://doi.org/10.1523/JNEUROSCI.2386-20.2021 Copyright {\textcopyright} 2021 the authors Publisher Copyright: {\textcopyright} 2021 Society for Neuroscience. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = feb,
day = "24",
doi = "10.1523/JNEUROSCI.2386-20.2021",
language = "English (US)",
volume = "41",
pages = "1650--1664",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "8",
}