Congenital heart malformation occurs in approximately 1% of all human live births and approximately 8% of stillbirths. Laterality defects, including heterotaxy and situs inversus, cause a significant portion of the morbidity and mortality of congenital heart malformations. The cardiac tube must loop appropriately to allow subsequent crucial events, such as septation, valve formation and outflow tract formation, to occur normally. Cardiac left-right development and normal cardiac looping are dependent on the synthesis and deposition of a class of transmembrane and extracellular proteins known as heparin sulfate proteoglycans (HSPGs) during specific periods in early Xenopus embryogenesis. The expression patterns of syndecans, a highly conserved class of HSPGs, implicate them in early embryonic cell-cell signaling that establishes the cardiac left-right axis, and serves as the starting point for this proposal. Two syndecan maternal RNAs are synthesized during oogenesis and exclusively localized in the specific cell lineages and during the defined periods of embryogenesis that are crucial for cardiac left-right orientation. Taking advantage of unique techniques in Xenopus embryology, experiments proposed here will test the hypothesis that syndecans are key modulators of the molecular signals that establish cardiac left-right asymmetry.
In Aim 1, maternal Xenopus syndecan mRNAs will be depleted and the effects of mesoderm induction, cardiac mesoderm formation and cardiac left-right orientation will be assessed both morphologically and with molecular markers.
In Aim 2, four molecular or embryological manipulations known to alter cardiac left-right development will be performed and the effects on syndecan expression will be assessed to, place the syndecans within the molecular pathway for cardiac pathway for cardiac left-right development.
In Aim 3, mutant forms of syndecans will be expressed in wild-type and syndecan-deficient embryos, in specific cell lineages, to define the molecular roles of conserved syndecan domain in the regulation of signals that establish cardiac left-right development. The long-term objective of this study is to discovered of the molecular mechanisms that regulated cardiac left-right development in Xenopus, in order to advance our understanding of genetic and environmental perturbations that results in congenital heart malformations in humans.
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