Genetic Dissection of Heart Development in the Fruit Fly Drosophila Melanogaster

The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. The Drosophila heart, known as the dorsal vessel, functions as a pulsatile tube-like organ containing an inner layer of contractile cardial cells that adhere tightly to an adjacent layer of pericardial cells. A genetic screen for genes that control Drosophila heart development revealed a cardiac defect in which pericardial and cardial cells dissociate causing loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in the genes encoding HMG-CoA Reductase, downstream enzymes in the mevalonate pathway, and G-protein Ggamma 1, which is geranylgeranylated, thus representing an endpoint of isoprenoid biosynthesis. These findings reveal a cardial cell-autonomous requirement of Ggamma 1 geranylgeranylation for heart formation and suggest the involvement of the mevalonate pathway in congenital heart disease. In addition, we found that the heterotrimeric G proteins Gbeta 13F and G-oalpha 47A together with the RGS (regulator of G protein signaling) protein Loco function in the same pathway as Ggamma 1 to regulate septate junction formation in cardial cells of the Drosophila heart. We also present evidence that the septate junction protein Sinuous interacts with Pericardin, a matrix protein secreted by pericardial cells, providing the molecular basis for cardial-pericardial cell adhesion and serving as a mediator of the actions of the mevalonate pathway and heterotrimeric G protein signaling in Drosophila heart development.