title: A hindbrain-repressive Wnt3a/Meis3/Tsh1 circuit promotes neuronal differentiation and coordinates tissue maturation.
abstract: During development, early inducing programs must later be counterbalanced for coordinated tissue maturation. In Xenopus laevis embryos, activation of the Meis3 transcription factor by a mesodermal Wnt3a signal lies at the core of the hindbrain developmental program. We now identify a hindbrain restricting circuit, surprisingly comprising the hindbrain inducers Wnt3a and Meis3, and Tsh1 protein. Functional and biochemical analyses show that upon Tsh1 induction by strong Wnt3a/Meis3 feedback loop activity, the Meis3-Tsh1 transcription complex represses the Meis3 promoter, allowing cell cycle exit and neuron differentiation. Meis3 protein exhibits a conserved dual-role in hindbrain development, both inducing neural progenitors and maintaining their proliferative state. In this regulatory circuit, the Tsh1 co-repressor controls transcription factor gene expression that modulates cell cycle exit, morphogenesis and differentiation, thus coordinating neural tissue maturation. This newly identified Wnt/Meis/Tsh circuit could play an important role in diverse developmental and disease processes.
authors.affiliation: Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Yaniv M
authors.initials: YM
authors.lastname: Elkouby
authors.forename: Hanna
authors.initials: H
authors.lastname: Polevoy
authors.forename: Yoni E
authors.initials: YE
authors.lastname: Gutkovich
authors.forename: Ariel
authors.initials: A
authors.lastname: Michaelov
authors.forename: Dale
authors.initials: D
authors.lastname: Frank
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D056970:Co-Repressor Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D012249:Rhombencephalon / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D060509:Wnt3A Protein / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins; C491174:Meis3 protein, Xenopus; D014157:Transcription Factors; D060509:Wnt3A Protein; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C518906:tshz1 protein, zebrafish