Establishment of Left-Right Asymmetry in Vertebrates: Genetically Distinct Steps are Involved

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Abstract
Vertebrates exhibit a characteristic pattern of asymmetrical positioning of the visceral organs along the left-right axis. A remarkable developmental step establishes this pattern--primitive organs migrate from symmetrical midline positions of origin into lateral positions. The first organ to pursue such movement is the cardiac tube, which forms a rightward 'D' loop; other organs follow concordantly. The signals and mechanisms directing such organ migration can be studied by analysis of heritable defects of humans and mice. In general, these defects behave as loss-of-function mutations that lead to random determination of visceral situs: for an affected embryo there is an equal chance of correct situs or situs inversus. Distinct phenotypes and patterns of inheritance of these defects suggest that at least three genes are involved in left-right determination, apparently members of a developmental pathway. These genes should be amenable to molecular analysis. We are studying a recessive allele of the mouse called inversus viscerum (iv). Using linkage analysis with cloned restriction fragment length polymorphism markers, we have genetically mapped the iv gene to the distal portion of mouse chromosome 12. We are now pursuing isolation of the gene using methods of positional cloning. Analysis of the iv gene product and of its site and timing of expression may offer clues to how left-right lateralization occurs.