Transcriptional repression by the T-box proteins tbx18 and tbx15 depends on groucho corepressors

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.