Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action

The TRAP220 component of the TRAP/SMCC complex, a mammalian homolog of the yeast Mediator that shows diverse coactivation functions, interacts directl y with nuclear receptors. Ablation of the murine Trap220 gene revealed that null mutants die during an early gestational stage with heart failure and exhibit impaired neuronal development with extensive apoptosis. Primary emb ryonic fibroblasts derived from null mutants show an impaired cell cycle re gulation and a prominent decrease of thyroid hormone receptor function that is restored by ectopic TRAP220 but no defect in activation by Gal4-RAR alp ha/RXR alpha, p53, or VP16. Moreover, haploinsufficient animals show growth retardation, pituitary hypothyroidism, and widely impaired transcription i n certain organs. These results indicate that TRAP220 is essential for a wi de range of physiological processes but also that it has gene- and activato r-selective functions.