Strong conservation of heart formation along the left-right (LR) axis among vertebrates suggests that common developmental mechanisms and genetic pathways exist for left-right development. However, despite abundant evidence supporting a role for nodal monocilia in the establishment of LR asymmetry, little is known about formation of the late gastrula node. In zebrafish, the node equivalent is Kupffer's vesicle (KV). KV contains monocilia, generates asymmetric fluid flow, and is necessary for left-sided expression of downstream laterality genes. Because KV is easily visualized and experimentally manipulated in zebrafish, the candidate will use this model system to better understand KV formation and its role in LR development. From preliminary studies, he has discovered that syndecan-2, a single-pass transmembrane heparan sulfate proteoglycan, is required for normal LR development and plays a cell-autonomous role in KV formation. Morpholino knockdown of syndecan-2 causes reversal of heart and gut looping and leads to misshapen KV with fewer and shorter cilia. Based on these observations, the candidate proposes to further define the role of syndecan-2 in KV and cilia formation/function and explore the necessary molecular interactions of syndecan-2 during the process of KV development. Through this study, genetic and molecular mechanisms that regulate cardiac LR development will be discovered and one day used to improve detection and treatment of congenital heart disease in children.
Abnormalities in left-right development often lead to complex congenital heart defects with significant associated morbidity and mortality, but little is known about the molecular anomalies that cause these defects. Understanding the mechanisms that regulate left-right development in model vertebrate systems will advance our ability to understand, detect, and treat human cardiovascular malformations.
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