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Disrupted Function of Tumor Necrosis Factor--Stimulated Gene 6 Blocks Cumulus Cell-Oocyte Complex Expansion

Department of Molecular and Cellular Biology (S.A.O., J.S.R.), Baylor College of Medicine, Houston, Texas 77030; Medical Research Council Immunochemistry Unit (A.J.D., M.S.R.), Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; Departments of Medicine (Division of Nephrology) and Pharmacology, Vanderbilt University School of Medicine (R.M.B.), Nashville, Tennessee 37232-2372; and Howard Hughes Medical Institute and Department of Biochemistry and Cell Biology (R.H.G.), Rice University, Houston, Texas 77005-1892

Address all correspondence and requests for reprints to: J. S. Richards, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: joanner{at}bcm.tmc.edu.

During ovulation, the oocyte and surrounding somatic cumulus cells contained within a specialized, mucoid matrix are released from the ovary. One matrix component, TNF--stimulated gene 6 (TSG-6), is a hyaluronan binding protein induced in cumulus cells of preovulatory follicles by the LH surge and is decreased in cumulus cells of COX-2 and prostaglandin E₂ (PGE₂) receptor subtype EP2 null mice that exhibit impaired ovulation and cumulus expansion. To determine if TSG-6 was hormonally induced in cumulus cells in vitro and was functional during the formation of the expanded matrix, we established a cumulus cell-oocyte complex (COC) culture system. This system was used to analyze the effects of FSH, PGE₂, EP2 receptor, and selected protein kinase inhibitors on TSG-6 production as well as specific antibodies to the TSG-6 link module on TSG-6 function. We document that TSG-6 message and protein are induced by cAMP/protein kinase A/MAPK signaling pathways and that blocking these cascades prevents expansion and the production of TSG-6. FSH but not PGE₂ rescued expansion and production of TSG-6 in the EP2 null COCs, indicating that generation of a cAMP signal is essential. Furthermore, disruption of the functional interactions between TSG-6, inter- trypsin inhibitor, and hyaluronan with specific antibodies severely altered matrix formation and cumulus expansion, as recorded by time-lapse imaging. Collectively, these results indicate that TSG-6 mRNA is induced in cumulus cells in culture by cAMP and that the secreted TSG-6 protein is a key structural component of the mouse COC matrix.

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