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      A Heterogeneous Mixture of F-Series Prostaglandins Promotes Sperm Guidance in the Caenorhabditis elegans Reproductive Tract

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          Abstract

          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 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.

          Author Summary

          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 . 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.

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          Most cited references46

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          Specific interference by ingested dsRNA.

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            Cyclooxygenases 1 and 2.

            Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
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              Progesterone activates the principal Ca2+ channel of human sperm.

              Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca(2+) influx into spermatozoa and triggers multiple Ca(2+)-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor. However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor. The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca(2+) entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of progesterone on human spermatozoa by identifying the Ca(2+) channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca(2+) channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                January 2013
                January 2013
                31 January 2013
                : 9
                : 1
                : e1003271
                Affiliations
                [1 ]Department of Cell Biology, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [2 ]Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                University of California San Francisco, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MAM JKP. Performed the experiments: HDH DD JKP. Analyzed the data: HDH JKP MAM. Wrote the paper: MAM HDH.

                Article
                PGENETICS-D-12-02590
                10.1371/journal.pgen.1003271
                3561059
                23382703
                c279456c-834e-49e8-ac8a-0ac4c5d0fdb8
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 October 2012
                : 10 December 2012
                Page count
                Pages: 15
                Funding
                This project was funded by the NIH NIGMS (R01GM085105 to MAM, including an ARRA Administrative Supplement and Research Supplement to Promote Diversity in Health-Related Research). The UAB Targeted Metabolomics and Proteomics Laboratory has been supported in part by the UAB Skin Disease Research Center (P30 AR050948), the UAB-UCSD O'Brien Acute Kidney Injury Center (P30 DK079337), the UAB Lung Health Center (R01 HL114439, R01 HL110950), and UAB Center for Free Radical Biology. Support for the mass spectrometer was from a NCRR Shared Instrumentation grant (S10 RR19261). The Caenorhabditis Genetics Center is supported by the NIH Office of Research Infrastructure Programs (P40 OD010440) and the Japanese National Bioresource Project is supported by the Ministry of Education, Culture, Science, Sports and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Lipids
                Fatty Acids
                Lipid Mediators
                Lipid Metabolism
                Developmental Biology
                Fertilization
                Sperm Chemotaxis
                Sperm-Egg Interactions
                Molecular Development
                Signaling

                Genetics
                Genetics

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