Oxysterol-binding protein (OSBP) was originally identified as a cytosolic protein that bound to an oxygenated cholesterol. OSBP is translocated from the cytosol to the Golgi in response to cellular sterol content, and recently it has been shown that OSBP facilitates the transfer of cholesterol between membranes in vitro, suggesting that OSBP mediates non-vesicular cholesterol transport to the Golgi. A family of OSBP-related proteins (ORP family) has been identified in a variety of species ranging from yeast to mammals. The ORP family members are also implied to be involved in cholesterol transport; however, the physiological functions in vivo remain to be elucidated. In this study, we generated the deletion mutants of all four ORP genes in C. elegans (obr-1-4). All single, double and triple obr mutants were viable and showed no apparent abnormalities. However, obr-1;obr-2;obr-3;obr-4 quadruple mutants lacking all obr genes exhibited embryonic lethality (~11%) and slow growth during larval development (~18%). Of the obr quadruple mutant embryos that did not hatch, the majority (94%) developed to the late embryonic stage (2- to 4-fold stage), indicating that there is no strict requirement for OBR proteins during early embryogenesis. Hatched obr quadruple mutants were able to develop to adults and produce subsequent progeny; however, they had a reduced brood size (60% of wild-type) and showed defects in gonadal cell migrations with incomplete penetrance (~10%). These data suggest that OBR proteins (OBR-1~4) act redundantly on embryonic development and larval growth in C. elegans. To gain insight into the molecular mechanisms of embryonic lethality in obr quadruple mutants, we conducted a synthetic lethal RNAi screen to identify genes which functionally compensate for the obr molecules. We tested 2434 RNAi clones in the Ahringer library and identified 28 genes that showed specific synthetic lethality in the obr quadruple mutant background, but not in the wild-type background. These enhancer genes include the genes encoding vesicular transport-related proteins, signaling proteins, and nuclear proteins. At the meeting, we will present detailed analysis of genetic interactions between obr and the enhancer genes.