A hindbrain-repressive Wnt3a/Meis3/Tsh1 circuit promotes neuronal differentiation and coordinates tissue maturation

• Published in: Development (Cambridge) Vol. 139; no. 8; pp. 1487 - 1497
• Main Authors: Elkouby, Yaniv M, Polevoy, Hanna, Gutkovich, Yoni E, Michaelov, Ariel, Frank, Dale
• Format: Journal Article
• Language: English
• Published: England 15.04.2012
• Subjects: Animals; beta Catenin - metabolism; Cell Differentiation; Co-Repressor Proteins - metabolism; Gene Expression Profiling; Gene Expression Regulation, Developmental; Homeodomain Proteins - metabolism; Neurons - metabolism; Open Reading Frames; Plasmids - metabolism; Rhombencephalon - metabolism; Transcription Factors - metabolism; Transcription, Genetic; Wnt3A Protein - metabolism; Xenopus; Xenopus laevis; Xenopus Proteins - metabolism; Zebrafish; Zebrafish Proteins - metabolism
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.072934

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.