Inherited defects in the degradation of sphingolipids cause a group of severe disorders known as sphingolipid storage diseases. Examples include Tay-Sachs, Sandhoff, Niemann-Pick and Gaucher diseases. There are currently no effective treatments for the majority of these diseases. Our work has focused on understanding disease pathogenesis in order to develop new therapeutic approaches. In this regard, we have demonstrated a potentially important role for activated macrophages in neuronal death in Sandhoff disease. This finding, if common, to other storage diseases may lead to new approaches to therapy. We are also investigating the functions of sphingolipids to learn their roles in disease processes. To this end we are systematically disrupting genes involved in sphingolipid metabolism in the mouse. Recently, we disrupted the gene for Edg-1, a G-protein coupled receptor that binds sphingosine-1-phosphate (SPP). Edg-1-/- mice exhibited embryonic hemorrhage leading to intrauterine death between E12.5 and E14.5. Vasculogenesis and angiogenesis appeared normal in the mutant embryos. However, vascular maturation was incomplete due to a deficiency of vascular smooth muscle cells/pericytes. We showed that Edg-1 mediates an SPP-induced migration response that is defective in mutant cells due to an inability to activate the small GTPase, Rac. Our data reveal Edg-1, as the first G-protein coupled receptor required for blood vessel formation and show that sphingolipid signaling is essential during mammalian development.
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