A heart segmental defect in the anterior-posterior axis of a transgenic mutant mouse.

A recessive lethal insertional mutation on chromosome 13 has been identified in a transgenic mouse line that displays a segmental form of cardiac defect along the anterior-posterior axis in all homozygous mice identified. The most anterior segment (future conus and right ventricle) of the single heart tube fails to develop normally and the endocardial cushions in both the conus and the atrioventricular regions are missing. Analysis of the beta-galactosidase reporter portion of the transgene during embryonic development shows a segmental expression of activity primarily in the defective outlet of the primitive heart. In addition to expression in the heart tube, hemizygous embryos show transgene expression in the chondrogenic regions of first and second branchial arches, the appendicular skeleton, and the dermal papillae of the vibrissae. The restricted pattern of beta-galactosidase expression in the heart can be disrupted with retinoic acid exposure and extended posteriorly along the anterior-posterior axis in hemizygous mice. Although cushion 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 trisomic for chromosome 13 have also been shown to display segmental anomalies associated with the anterior primitive outlet segments of the heart. 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 development of the anterior limb of the developing heart. The hdf mouse mutation also provides a new model system to evaluate the molecular requirements of normal endocardial cushion formation and the segmental interactions that form the adult heart.