Activator-to-repressor conversion of T-box transcription factors by the Ripply family of Groucho/TLE-associated mediators

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

^* To whom correspondence should be addressed. Email: stakada{at}nibb.ac.jp.

	Abstract

The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulates 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 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 the 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.