The vertebrate heart is formed during embryogenesis from a cardiac tube that loops in a highly conserved orientation along the left-right axis. This looping brings together the inflow and outflow tracts and positions the segments of the heart tube, allowing subsequent remodeling to give rise to crucial structures such as septa and valves. The bilaterally symmetric gut primordium gives rise to asymmetrically positioned liver, gall bladder, pancreas, spleen, stomach and intestines. The strong conservation of left-right orientation of these internal organs suggests that common developmental mechanisms and genetic pathways for left-right development will be found in all vertebrates. Although the new field of left-right development has progressed rapidly in the last few years and discovered several significant genes that are expressed asymmetrically during embryogenesis, the cellular and molecular mechanisms that initiate left-right axis formation are poorly understood. Using embryos of the frog Xenopus laevis, we found that the earliest steps in left-right axis formation are driven by a balance between two closely related but mutually antagonistic signaling pathways in the TGF-beta superfamily: Vgl on the left and BMP2/4 on the right in the blastula stage embryo. Perturbations in these pathways alter downstream asymmetric gene expression and disrupt heart and gut left-right morphogenesis.
Aim 1 uses a new technique of cell-lineage specific gene """"""""knockdown"""""""" to study the regulation of these antagonistic pathways.
Aim 2 uses a high throughput, genome-wide functional screen to identify novel genes that regulate left-right axis formation. Based on one of the genes discovered in the preliminary test of this screen, Aim 3 will elucidate the role of Ubiquitinmediated proteolysis in left-right development. In an attempt to reconcile the view that mammalian left-right development is initiated by a different mechanism than frog and chick left-right development, Aim 4 will test whether Xenopus Left-Right Dynein, expressed in the embryonic node, modulates the TGF-beta signaling pathways implicated in left-right development. Together, these aims elucidate the earliest steps in embryonic left-right axis formation that lead to heart and gut asymmetric morphogenesis.
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