Title:
Prostaglandin E2 -EP2 signaling regulates cumulus extracellular matrix status for successful fertilization
Yukihiko Sugimoto, Ph.D.
Department of Pharmaceutical Biochemistry, Kumamoto University
Abstract:
The cumulus oophorus (cumulus cells and extracellular matrix (ECM)) makes a tight complex with an oocyte, and is ovulated together as the cumulus-oocyte complex. Recent studies suggested that the cumulus ECM, dynamically regulated by microenvironments, is required for successful fertilization in vivo. However, little is known about the signaling therein. Prostaglandin E 2 (PGE 2 ) is one of major arachidonate metabolites and plays essential roles in physiological and pathological settings. PGE receptor EP2-deficient ( EP2 -/- ) female mice exhibit a severe fertilization defect. We examined the molecular events leading to this failure. We found that expression of chemokine gene is induced in cumulus cells surrounding the egg after ovulation, and is augmented in EP2 -/-cumuli. While these chemokines function to attract sperm to cumuli, the exogenous addition of these chemokines to wild type cumulus-egg complexes induces fertilization failure in vitro , and the addition of a CCL7 receptor antagonist improves fertilization rates in EP2 -/- complexes. Cumulus cells from EP2 -/- mice and those treated with CCL7 in vitro show RhoA-dependent cell contraction, and enhanced integrin expression and binding to the ECM which confer these cumuli with resistance to hyaluronidase treatment and thus prevent sperm penetration. These results suggest that PGE 2 -EP2 signaling negatively regulates chemokine-induced integrin engagement to the ECM and allows sperm penetration through cumulus matrices, and this interaction between PG and chemokine signaling is required for successful fertilization.
References:
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