Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensures proper maturation timing. These results reveal genes regulating steroidogenesis during development that likely modulate disease mechanisms.
Bibliographical noteFunding Information:
We thank the people who contributed reagents. This work was supported by a Danish Council for Independent Research, Natural Sciences grant (11-105446) and by a Novo Nordisk Foundation grant (10929) to K.F.R. M.B.O., K.A.O., and M.J.H. were supported by NIH grant GM093301 to M.B.O. N.Y. was supported by NIH grants K99/R00 HD073239 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).