Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation

Chuntao Zhao, Yaqi Deng, Lei Liu, Kun Yu, Liguo Zhang, Haibo Wang, Xuelian He, Jincheng Wang, Changqing Lu, Laiman N Wu, Qinjie Weng, Meng Mao, Jianrong Li, Johan H van Es, Mei Xin, Lee Parry, Steven A Goldman, Hans Clevers and Q. Richard Lu ()
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Chuntao Zhao: State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Yaqi Deng: State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Lei Liu: State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Kun Yu: State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Liguo Zhang: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Haibo Wang: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Xuelian He: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Jincheng Wang: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Changqing Lu: State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Laiman N Wu: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Qinjie Weng: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University
Meng Mao: Key Laboratory of Obstetrics, and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy
Jianrong Li: Texas A&M University, College Station, Texas 77843, USA
Johan H van Es: Hubrecht Institute, Uppsalalaan 8, Utrecht 3584CT, The Netherlands
Mei Xin: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center
Lee Parry: European Cancer Stem Cell Research Institute, Cardiff University
Steven A Goldman: Center for Translational Neuromedicine, University of Rochester Medical Center
Hans Clevers: Hubrecht Institute, Uppsalalaan 8, Utrecht 3584CT, The Netherlands
Q. Richard Lu: Brain Tumor Center, Cincinnati Children’s Hospital Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Constitutive activation of Wnt/β-catenin inhibits oligodendrocyte myelination. Tcf7l2/Tcf4, a β-catenin transcriptional partner, is required for oligodendrocyte differentiation. How Tcf7l2 modifies β-catenin signalling and controls myelination remains elusive. Here we define a stage-specific Tcf7l2-regulated transcriptional circuitry in initiating and sustaining oligodendrocyte differentiation. Multistage genome occupancy analyses reveal that Tcf7l2 serially cooperates with distinct co-regulators to control oligodendrocyte lineage progression. At the differentiation onset, Tcf7l2 interacts with a transcriptional co-repressor Kaiso/Zbtb33 to block β-catenin signalling. During oligodendrocyte maturation, Tcf7l2 recruits and cooperates with Sox10 to promote myelination. In that context, Tcf7l2 directly activates cholesterol biosynthesis genes and cholesterol supplementation partially rescues oligodendrocyte differentiation defects in Tcf712 mutants. Together, we identify stage-specific co-regulators Kaiso and Sox10 that sequentially interact with Tcf7l2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development, and point to a previously unrecognized role of Tcf7l2 in control of cholesterol biosynthesis for CNS myelinogenesis.

Date: 2016
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DOI: 10.1038/ncomms10883

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