The wnt effector tcf7l2 promotes oligodendroglial differentiation by repressing autocrine bmp4-mediated signaling

Sheng Zhang, Yan Wang, Xiaoqing Zhu, Lanying Song, Xinhua Zhan, Edric Ma, Jennifer McDonough, Hui Fu, Franca Cambi, Judith Grinspan, Fuzheng Guo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1650-1664
Number of pages15
JournalJournal of Neuroscience
Volume41
Issue number8
DOIs
StatePublished - Feb 24 2021

Keywords

  • Bmp4 repression
  • Canonical wnt/b-catenin
  • Myelination
  • Oligodendrocyte differentiation
  • Tcf7l2/tcf4
  • Wnt effector

ASJC Scopus subject areas

  • Neuroscience(all)

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