Abstract 786: Hand Genes in the Mammalian Heart Chamber Formation
Hand genes (Hand1/eHand and Hand2/dHand) encode critical transcription factors required for cardiovascular development. Hand1 and Hand2 are complementally expressed during the murine heart development; Hand2 is expressed throughout the heart predominantly in right ventricle, whereas Hand1 is restricted in left ventricle. Although Hand1 null (Hand1−/−) mice die before the cardiac looping, cardiac-specific Hand1−/− mice survive until birth and display defects in left ventricle and endocardial cushion. Hand2 null (Hand2−/−) mice die at embryonic day (E) 10.5 due to the heart failure and display severe hypoplasia of right ventricle poor trabeculation in left ventricle along with developmental defects of pharyngeal arches and limb buds. To delineate the genetic redundancy and regional function of Hand genes in ventricular development we generated genetically engineered Hand2Hand1/Hand1 mice where a Hand2 gene was replaced by the Hand1 cDNA using homologous recombination so that Hand1, but not Hand2, was driven under control of endogenous Hand2 promoter, and Hand2Hand1/− mice from mating of Hand2Hand1/+ mice with Hand2+/− mice. Our observation reveled that Hand2Hand1/Hand1 mice had hypoplastic right ventricle, but no sign of heart failure before E12.5, and survived until E13.5. This phenotype was milder than that of Hand2−/− or Hand2Hand1/− mice, suggesting that Hand1 could partially compensate the function of Hand2 in ventricular formation. In contrast, pharyngeal arch development was not affected until E13.5 whereas developmental arrest was observed in the posterior region of limb buds where Hand2 regulates the Sonic hedgehog expression. These results indicate that in mammalian heart, Hand genes may have common function and partial genetic redundancy for ventricular formation, and that Hand genes are genetically redundant in tissue-specific manner during murine development. The complementally expression of Hand genes may be essential for regionalization of right and left ventricles.