The vertebrate body plan has highly conserved left-right asymmetries in many of the internal organs, including the heart, brain, lungs and viscera (stomach, liver, spleen, gall bladder and intestinal coil). Abnormal left-right development of any of these organs with respect to the others is called discordance, and often has sever pathology. Studies in several model vertebrate systems have implicated over thirty-five genes in left-right development, predominantly in cardiac development. Many of these genes are expressed in the embryonic node and midline, which control much of dorsal-ventral and anterior- posterior development. Both embryological experiments and analysis of mutants support eh central role of the node and midline in left-right development. Thus, it is likely that the three-dimensional organism (with left-right, anterior-posterior and dorsal-ventral asymmetries) is built by specific organizing centers in the node and midline. However, little is known about the genetic pathways or developmental mechanisms that coordinate the concordant development of left-right orientation in multiple organs throughout the body plan. None of the models for the mechanisms by which midline cells regulate left-right development are capable of explaining the diverse laterality defects that are seen in humans and in model organisms. The proposed research uses a combination of zebrafish genetics, molecular biology, embryological manipulations, and meta-analysis of a large collection of laterality mutants with molecular markers for asymmetry in the heart, brain and viscera. The goal is to discover the genetic pathways and mechanisms by which the organ primordia throughout the body plan are given instructions for concordant left-right development. Our working hypothesis, supported by preliminary observations and recent publications, is that distinct genetic pathways, expressed in specific domains of midline cells along the anterior-posterior axis of the embryo, regulate the concordant left-right development of the heart, brain and viscera.
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