title: Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.
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.
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.|Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Chuntao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.|Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.|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, Chengdu 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.|Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Lu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Laiman N
authors.initials: LN
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.affiliation: 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, Chengdu 610041, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.affiliation: Hubrecht Institute, Uppsalalaan 8, Utrecht 3584CT, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF244HQ, UK.
authors.forename: Lee
authors.identifier: http://orcid.org/0000-0002-4467-9196
authors.initials: L
authors.lastname: Parry
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, 601 Elmwood Avenue Rochester, New York 14642, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
authors.affiliation: Hubrecht Institute, Uppsalalaan 8, Utrecht 3584CT, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.|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, Chengdu 610041, China.|Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009420:Nervous System / Q000254:growth & development* / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D011485:Protein Binding; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C118822:Zbtb33 protein, mouse