The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. To identify novel cardiogenic genes, we performed a large-scale genetic screen in Drosophila. We discovered a unique cardiac defect, called broken hearted (bro), in which pericardial cells and cardioblasts dissociate, causing loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in genes encoding HMG-CoA reductase and its downstream enzymes in the mevalonate pathway, as well as G protein G31, which is geranylgeranylated, thus representing an end point of isoprenoid biosynthesis. Identification of the essential role of C in cardiac morphogenesis opened a door to discovery of the entire G protein genetic pathway required for cardiac morphogenesis. Here, we will investigate the functional mechanism of G31, and identify the G1 and G2 partners that form the cardiac heterotrimeric G protein complex with G31. From our screen, we also identified two G-protein coupled receptors (GPCRs) involved in this process. We will investigate the roles of these GPCRs using cardiac cell type specific rescue system established in our preliminary studies. Our screen also identified two bro mutations disrupting genes encoding septate junction components, indicating that septate junction formation is involved in cardiac morphogenesis. We will characterize the cell-cell junctions of Drosophila heart using electron microscopy and study the role of septate junction proteins during heart development. We will also examine how the G protein signaling mutants affect septate junction formation in the heart. These studies will fill a significant gap in the research field of heart development, and promote our understanding of the molecular mechanism of congenital heart disease. Narrative: Heart development is controlled by evolutionarily conserved genetic network. To identify genes in this network, we performed a large-scale genetic screen in Drosophila and identified a group of highly conserved genes required for heart formation. Studies of these genes promote our understanding of heart development and mechanism of congenital heart disease.
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