The mechanisms that guide motile sperm through the female reproductive tract to oocytes are not well understood. We have shown that Caenorhabditis elegans oocytes synthesize sperm guiding F-series prostaglandins from polyunsaturated fatty acid (PUFA) precursors provided in yolk lipoprotein complexes. Here we use genetics and electrospray ionization tandem mass spectrometry to partially delineate F-series prostaglandin metabolism pathways. We show that omega-6 and omega-3 PUFAs, including arachidonic and eicosapentaenoic acids, are converted into more than 10 structurally related F-series prostaglandins, which function collectively and largely redundantly to promote sperm guidance. Disruption of omega-3 PUFA synthesis triggers compensatory up-regulation of prostaglandins derived from omega-6 PUFAs. C. elegans F-series prostaglandin synthesis involves biochemical mechanisms distinct from those in mammalian cyclooxygenase-dependent pathways, yet PGF 2α stereoisomers are still synthesized. A comparison of F-series prostaglandins in C. elegans and mouse tissues reveals shared features. Finally, we show that a conserved cytochrome P450 enzyme, whose human homolog is implicated in Bietti's Crystalline Dystrophy, negatively regulates prostaglandin synthesis. These results support the model that multiple cyclooxygenase-independent prostaglandins function together to promote sperm motility important for fertilization. This cyclooxygenase-independent pathway for F-series synthesis may be conserved.
A fundamental question in cell and developmental biology is how motile cells find their target destinations. One of the most important cell targeting mechanisms involves the sperm and oocyte, which unite during fertilization to produce the next generation of offspring. We have been using the nematode C. elegans to delineate these mechanisms. Our prior studies have shown that oocytes secrete F-series prostaglandins that stimulate sperm motility. Prostaglandins are widespread signaling molecules derived from polyunsaturated fatty acids or PUFAs. Mammals are not capable of synthesizing PUFAs and must receive them in the diet. C. elegans was not thought to synthesize prostaglandins because the genome lacks cyclooxygenases, enzymes that catalyze the rate-limiting step in mammalian prostaglandin synthesis. Here we show that C. elegans oocytes synthesize a heterogenous mixture of structurally related F-series prostaglandins derived from different PUFA classes, including the enantiomer of PGF 2α. These prostaglandins function collectively and redundantly to guide sperm to the fertilization site. Our results indicate that F-series prostaglandins can be synthesized independent of cyclooxygenase enzymes. This novel pathway may be evolutionarily conserved. Evidence is emerging that prostaglandins regulate sperm motility in the female reproductive tract of humans.