GENE THAT CONTROLS LATERALITY IN EARLY CARDIOGENESIS

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We will address the fundamental role of bilateral symmetry in normal and abnormal cardiogenesis by anatomic, biochemical and genetic investigations of the autosomal recessive iv/iv mouse mutant. The iv/iv mouse is a recognized model of human situs inversus and polysplenia-asplenia syndrome, demonstrating random sidedness of the heart and other viscera, as well as a high frequency of cardiac malformations such as complete AV canal, transposition of the great arteries, and double outlet right ventricle. We will also utilize an experimental avian model. These models will permit us to make baseline studies of normal development as well as begin to discern the mechanisms that can cause human malformations, arteries, and double outlet right ventricle. Extrapolation to human congenital heart defects will utilize the availability of human autosomal recessive mutations whose phenotype parallels the mouse mutant. This work will have four main thrusts: 1. To determine paterns of inheritance of situs inversus and heterotaxia in selected inbred strains homozygous for iv. Particular attention will be paid to SWV-iv where the gene occasionally shows a dominant effect. 2. To identify polypeptides uniquely synthesized during determination of embryonic laterality and use them in an attempt to clone the gene. We will determine if the iv gene is linked to any homeo box cluster. We will construct a genic (cDNA) library from 8 day mouse embryos and attempt to isolate the iv gene from this library. 3. To discern the relation between gene action and cardiovascular morphogenesis. We will study the laterality of myocardial cytodifferentiation in d and l rotated (both genetic and experimental) hearts to see if the genetic program for myosin expression is reversed in l loop. Since these mice have a high incidence of CAVC (an endocardial cushion defect), the morphological consequences of expression of this gene will be examined in cushion development both morphologically and experimentally. 4. To test models of heart looping utilizing both the genetic defect and an experimental avian system.