The role of Hand genes for the cardiac ventricular developinent and regionalization

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Hand genes (Hand1/eHand and Hand2/dHand) encode critical transcription factors required for cardiovascular and pharyngeal development. Hand2 is expressed predominantly in developing right ventricle, whereas Hand1 is restricted in left ventricle. Both Hand genes direct overlapping expression in pharyngeal arch mesenchyme. Hand1 null cardiac-specific null mice display defects in left ventricle and endocardial cushion. Hand2 null (Hand2^<-/->) mice display severe hypoplasia of right ventricle and die at embryonic day (E) 10.5 due to the heart failure resulting in degenerative pharyngeal arch and limb buds. To delineate the genetic redundancy and regional function of Hand genes in murine development we genetically engineered Hand2^<Hand1/Hand1> mice where Hand2 gene was replaced by the Hand1 cDNA using homologous recombination so that Hand1 was driven under control of endogenous Hand2 promoter. We also generated Hand2^<Hand1/-> mice from mating of Hand2^<Hand1/+> mice with Hand2^<+/-> mice. Our observation reveled that Hand2^<Hand1/Hand1>mice had hypoplastic right ventricle and preserved pharyngeal arch and survived until E13.5. This phenotype was milder than that of Hand2^<-/->or Hand2^<Hand1/-> mice. These findings suggest that Hand1 could partially compensate the function of Hand2 in ventricular and pharyngeal arch formations in a dose dependent fashion during development. These results indicate that in mammalian cardiac ventricles and pharyngeal arch, Hand genes may have common function and partial genetic redundancy. The complementally expression of Hand genes may be essential for regionalization of right and left ventricles.