A "Block and Rescue" Pharmacogenetic Approach to Dissecting a Biochemical Pathway Controlling Germ Cell Migration

Specific small molecule inhibitors of the de novo cholesterol synthesis pathway (statins) and the protein prenylation pathway were used to study their effect on germ cell migration. Hydroxymethylglutaryl-Coenzyme A reductase (HMGCoAR) catalyzes the rate-limiting step in the mevalonate pathway that produces isoprenoids and cholesterol. Pharmacological HMGCoAR inhibition by statins alters zebrafish development and germ cell migration. These effects were completely blocked by prior injection of mevalonate, the product of HMGCoAR activity, or the prenylation precursors farnesol and geranylgeraniol. Finally, pharmacological inhibition of geranylgeranyl transferase I activity, an enzyme downstream from mevalonate synthesis and responsible for the transfer of a lipid to target proteins, resulted in abnormal germ cell migration. These data together with new data from Drosophila demonstrate that protein prenylation is an evolutionarily conserved pathway mediating germ cell migration. Further, pharmacological block-and-rescue approach provided detailed information about the elements of isoprenoid biosynthesis that contribute to germ cell migration. A key question raised by this work is the identity of the prenylated protein which facilitates proper germ cell migration. Work from other laboratories suggests that germ cell migration might be a general model for the long-range migration of other cell types including cancer metastasis.