Prostaglandins in C. elegans Fertilization

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DESCRIPTION (provided by applicant): Dietary components and environmental exposures can impact gamete function and fertility, but the underlying mechanisms are poorly understood. Prostaglandins are locally acting lipid hormones derived from essential dietary fats. In the human ovary, prostaglandins are thought to promote multiple processes critical for fertilization and may have a direct effect on sperm function. Their precise roles and regulatory mechanisms have been difficult to delineate, however. The nematode C. elegans is a powerful, yet simple model to investigate prostaglandins in reproduction. Results from the previous funding period have shown that C. elegans oocytes synthesize multiple structurally related F-series prostaglandins, including PGF1¿ and PGF2¿ stereoisomers. These prostaglandins function collectively and partially redundantly to guide sperm to the fertilization site, thereby increasing reproductive output. Strong preliminary evidence provided in this proposal supports the model that food-derived and other environmental cues perceived by ciliated sensory neurons are key regulators of ovarian prostaglandin synthesis. These external cues are known to modulate expression of a transforming growth factor beta (TGF-¿) homolog called DAF-7 in head ASI sensory neurons. The objective of this proposal is to delineate the mechanism by which female food-sensing neurons regulate sperm function. The central hypothesis is that ASI sensory neurons secrete DAF-7/TGF-¿ to promote the synthesis of oocyte prostaglandins, which act via multiple G protein-coupled receptors (GPCRs) to stimulate sperm guidance. Aim 1 proposes to delineate a mechanism by which female sensory neurons regulate sperm motility. The working hypothesis is that adult sensory neurons secrete DAF-7/TGF-¿ to initiate a neuroendocrine signal transduction mechanism triggering prostaglandin synthesis in oocytes. Aim 2 proposes to delineate the mechanism by which sperm transduce prostaglandin signals. The working hypothesis is that oocyte F-series prostaglandins act via multiple SRB class GPCRs upstream of Gq. These studies may reveal that food-derived cues are transmitted from sensory neurons in the female brain to the reproductive tract through conserved hormone networks that control sperm motility. Disrupting these female neuroendocrine mechanisms, either through genetic mutation, dietary changes, or environmental exposures, could impair sperm function. In addition, the results are likely to uncover new prostaglandin functions and regulatory mechanisms. Abnormal neuron to sperm signaling could contribute to infertility in humans and livestock.