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J. Biol. Chem., Vol. 282, Issue 35, 25748-25759, August 31, 2007

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Transcriptional Repression by the T-box Proteins Tbx18 and Tbx15 Depends on Groucho Corepressors^*

From the Institute for Molecular Biology, Medizinische Hochschule Hannover, 30625 Hannover, Germany

Tbox18 (Tbx18) and Tbox15 (Tbx15) encode a closely related pair of vertebrate-specific T-box (Tbx) transcription factors. Functional analyses in the mouse have proven the requirement of Tbx15 in skin and skeletal development and of Tbx18 in the formation of the vertebral column, the ureter, and the posterior pole of the heart. Despite the accumulation of genetic data concerning the embryological roles of these genes, it is currently unclear how Tbx18 and Tbx15 exert their function on the molecular level. Here, we have initiated a molecular analysis of Tbx18 and Tbx15 proteins and have characterized functional domains for nuclear localization, DNA binding, and transcriptional modulation. We show that both proteins homo- and heterodimerize, bind to various combinations of T half-sites, and repress transcription in a Groucho-dependent manner. Competition with activating T-box proteins may constitute one mode of action as we show that Tbx18 interacts with Gata4 and Nkx2-5 and competes Tbx5-mediated activation of the cardiac Natriuretic peptide precursor type a-promoter and that ectopic expression of Tbx18 down-regulates Tbx6-activated Delta-like 1 expression in the somitic mesoderm in vivo.

Received for publication, May 4, 2007 , and in revised form, June 21, 2007.

^* This work was supported by a grant from the European Union FP6 contract "HeartRepair" (LSHM-CT-2005-018630), by grants from the German Research Council (DFG) and by the DFG-funded cluster of excellence "REBIRTH." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Medizinische Hochschule Hannover, Institute for Molecular Biology, OE5250, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-5324017; Fax: 49-511-5324283; E-mail: kispert.andreas{at}mh-hannover.de.

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