Abstract 685: Hand2 Is Required for Second Heart Field Development During Cardiogenesis
The basic helix loop helix (bHLH) family of transcription factors plays important roles in the determination and differentiation of multiple organs during development. Hand2, also known as dHAND, is a bHLH protein expressed throughout the heart with dominant expression in the right ventricular segment derived from the second heart field. Hand2-null embryos die around E10.5 due to heart failure and display severe hypoplasia of the right ventricle and poor trabeculation in the left ventricle. However, the early embryonic lethality of the Hand2-null embryos has precluded the study of its function in heart development at later stages. To determine the function of Hand2 in specific domains and at later stages of cardiogenesis, we generated mice with loxP sites surrounding the Hand2 gene. Hand2-loxp mice were mated with four different cardiac-specific Cre linesâ∈”Tbx1Cre, Mef2cCre, and Isl1Cre, which excise floxed genes in the second heart field, and Nkx2.5Cre, which is active in both right and left ventricles. The resulting tissue-specific mutants are all embryonic lethal, but survive longer than Hand2-null mutants. We observed that tissue-specific Hand2 mutants had various degrees of right ventricular and outflow tract defects. Tbx1Cre:Hand2 mutants died around E15.5 and displayed conotruncal defects with a small right ventricle. Mef2cCre:Hand2 mutants died around E13.5 with a muscular defect of both ventricles. Nkx2.5Cre:Hand2 mutants died around E12.5 and displayed a more severe ventricular muscle defect than Mef2cCre:Hand2 mutants. Isl1Cre:Hand2 mutants died around E10.5 with a ventricular defect phenocopying Hand2-null mutants. These results suggest a critical function of Hand2 in the second heart field and its derivatives. Analyses of gene expression alterations and relationship of mutants to defects in second heart field development will be presented.