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Activator-to-Repressor Conversion of T-Box Transcription Factors by the Ripply Family of Groucho/TLE-Associated Mediators ^,

Akinori Kawamura,^1,2,3 Sumito Koshida,^1,4, and Shinji Takada^1,4*

Okazaki Institute for Integrative Biosciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan,¹ Graduate School of Science and Engineering, Bioscience and Biomedical Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8050, Japan,² Department of Life Science, Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama 338-8570, Japan,³ Department of Basic Biology, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi 444-8787, Japan⁴

Received 25 September 2007/ Returned for modification 26 November 2007/ Accepted 28 February 2008

The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulate various aspects of embryogenesis by activating and/or repressing downstream genes. In spite of the biological significance of the T-box proteins, how they regulate transcription remains to be elucidated. Here we show that the Groucho/TLE-associated protein Ripply converts T-box proteins from activators to repressors. In cultured cells, zebrafish Ripply1, an essential component in somite segmentation, and its structural relatives, Ripply2 and -3, suppress the transcriptional activation mediated by the T-box protein Tbx24, which is coexpressed with ripply1 during segmentation. Ripply1 associates with Tbx24 and converts it to a repressor. Ripply1 also antagonizes the transcriptional activation of another T-box protein, No tail (Ntl), the zebrafish ortholog of Brachyury. Furthermore, injection of a high dosage of ripply1 mRNA into zebrafish eggs causes defective development of the posterior trunk, similar to the phenotype observed in homozygous mutants of ntl. A mutant form of Ripply1 defective in association with Tbx24 also lacks activity in zebrafish embryos. These results indicate that the intrinsic transcriptional property of T-box proteins is controlled by Ripply family proteins, which act as specific adaptors that recruit the global corepressor Groucho/TLE to T-box proteins.

Published ahead of print on 10 March 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan.