Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors

GATA-family transcription factors are critical to the development of divers e tissues. In particular, GATA-4 has been implicated in formation of the ve rtebrate heart, As the mouse Gata-4 knock-out is early embryonic lethal bec ause of a defect in ventral morphogenesis, the in vivo function of this fac tor in heart development remains unresolved. To search for a requirement fo r Gata4 in heart development, we created mice harboring a single amino acid replacement in GATA-4 that impairs its physical interaction with its presu mptive cardiac cofactor FOG-2. Gata4(ki/ki) mice die just after embryonic d ay (E) 12.5 exhibiting features in common with Fog2(-/-) embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventr icle. These findings establish an intrinsic requirement for GATA-4 in heart development. We also infer that GATA-4 function is dependent on interactio n with FOG-2 and, very likely, an additional FOG protein for distinct aspec ts of heart formation.