A HEART SEGMENTAL DEFECT IN THE ANTERIOR-POSTERIOR AXIS OF A TRANSGENIC MUTANT MOUSE

A recessive lethal insertional mutation on chromosome 13 has been iden tified in a transgenic mouse line that displays a segmental form of ca rdiac defect along the anterior-posterior axis in all homozygous mice identified. The most anterior segment (future conus and right ventricl e) of the single heart tube fails to develop normally and the endocard ial cushions in both the conus and the atrioventricular regions are mi ssing. Analysis of the P-galactosidase reporter portion of the transge ne during embryonic development shows a segmental expression of activi ty primarily in the defective outlet of the primitive heart. In additi on to expression in the heart tube, hemizygous embryos show transgene expression in the chondrogenic regions of first and second branchial a rches, the appendicular skeleton, and the dermal papillae of the vibri ssae. The restricted pattern of beta-galactosidase expression in the h eart can be disrupted with retinoic acid exposure and extended posteri orly along the anterior-posterior axis in hemizygous mice. Although cu shion mesenchyme fail to form in the homozygous mutant, the myocardial and endothelial cells explanted from the mutant atrioventricular, but not the conus, are capable of forming mesenchyme in vitro. Mice triso mic for chromosome 13 have also been shown to display segmental anomal ies associated with the anterior primitive outlet segments of the hear t. Our data show that this insertional mutation identifies a new gene locus, hdf (heart defect), on mouse chromosome 13 that may be required for mechanisms that initially establish and/or maintain continued dev elopment of the anterior limb of the developing heart. The hdf mouse m utation also provides a new model system to evaluate the molecular req uirements of normal endocardial cushion formation and the segmental in teractions that form the adult heart. (C) 1997 Academic Press.