This Article Full Text Full Text (PDF) Supplemental movies Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ochsner, S. A. Articles by Richards, J. S. Search for Related Content PubMed PubMed Citation Articles by Ochsner, S. A. Articles by Richards, J. S.

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.

This article has been cited by other articles:

				D. Haouzi, S. Assou, K. Mahmoud, B. Hedon, J. De Vos, D. Dewailly, and S. Hamamah LH/hCGR gene expression in human cumulus cells is linked to the expression of the extracellular matrix modifying gene TNFAIP6 and to serum estradiol levels on day of hCG administration Hum. Reprod., November 1, 2009; 24(11): 2868 - 2878. [Abstract] [Full Text] [PDF]

				H. He, W. Li, D. Y. Tseng, S. Zhang, S.-Y. Chen, A. J. Day, and S. C. G. Tseng Biochemical Characterization and Function of Complexes Formed by Hyaluronan and the Heavy Chains of Inter-{alpha}-inhibitor (HC{middle dot}HA) Purified from Extracts of Human Amniotic Membrane J. Biol. Chem., July 24, 2009; 284(30): 20136 - 20146. [Abstract] [Full Text] [PDF]

				Z. Liu, D. G. de Matos, H.-Y. Fan, M. Shimada, S. Palmer, and J. S. Richards Interleukin-6: An Autocrine Regulator of the Mouse Cumulus Cell-Oocyte Complex Expansion Process Endocrinology, July 1, 2009; 150(7): 3360 - 3368. [Abstract] [Full Text] [PDF]

				K. W. Sanggaard, C. S. Sonne-Schmidt, T. P. Krogager, T. Kristensen, H.-G. Wisniewski, I. B. Thogersen, and J. J. Enghild TSG-6 Transfers Proteins between Glycosaminoglycans via a Ser28-mediated Covalent Catalytic Mechanism J. Biol. Chem., December 5, 2008; 283(49): 33919 - 33926. [Abstract] [Full Text] [PDF]

				Q. Li, S. A. Pangas, C. J. Jorgez, J. M. Graff, M. Weinstein, and M. M. Matzuk Redundant Roles of SMAD2 and SMAD3 in Ovarian Granulosa Cells In Vivo Mol. Cell. Biol., December 1, 2008; 28(23): 7001 - 7011. [Abstract] [Full Text] [PDF]

				D. J. Mahoney, K. Mikecz, T. Ali, G. Mabilleau, D. Benayahu, A. Plaas, C. M. Milner, A. J. Day, and A. Sabokbar TSG-6 Regulates Bone Remodeling through Inhibition of Osteoblastogenesis and Osteoclast Activation J. Biol. Chem., September 19, 2008; 283(38): 25952 - 25962. [Abstract] [Full Text] [PDF]

				M. Shimada, Y. Yanai, T. Okazaki, N. Noma, I. Kawashima, T. Mori, and J. S. Richards Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization Development, June 1, 2008; 135(11): 2001 - 2011. [Abstract] [Full Text] [PDF]

				E. Nagyova, A. Camaioni, R. Prochazka, A. J. Day, and A. Salustri Synthesis of Tumor Necrosis Factor Alpha-Induced Protein 6 in Porcine Preovulatory Follicles: A Study with A38 Antibody Biol Reprod, May 1, 2008; 78(5): 903 - 909. [Abstract] [Full Text] [PDF]

				S. Cecconi, A. Mauro, G. Capacchietti, P. Berardinelli, N. Bernabo, A. R. Di Vincenzo, M. Mattioli, and B. Barboni Meiotic Maturation of Incompetent Prepubertal Sheep Oocytes Is Induced by Paracrine Factor(s) Released by Gonadotropin-Stimulated Oocyte-Cumulus Cell Complexes and Involves Mitogen-Activated Protein Kinase Activation Endocrinology, January 1, 2008; 149(1): 100 - 107. [Abstract] [Full Text] [PDF]

				Y. Yamashita, I. Kawashima, Y. Yanai, M. Nishibori, J. S. Richards, and M. Shimada Hormone-Induced Expression of Tumor Necrosis Factor {alpha}-Converting Enzyme/A Disintegrin and Metalloprotease-17 Impacts Porcine Cumulus Cell Oocyte Complex Expansion and Meiotic Maturation via Ligand Activation of the Epidermal Growth Factor Receptor Endocrinology, December 1, 2007; 148(12): 6164 - 6175. [Abstract] [Full Text] [PDF]

				M. Shimada, Y. Yanai, T. Okazaki, Y. Yamashita, V. Sriraman, M. C. Wilson, and J. S. Richards Synaptosomal-Associated Protein 25 Gene Expression Is Hormonally Regulated during Ovulation and Is Involved in Cytokine/Chemokine Exocytosis from Granulosa Cells Mol. Endocrinol., October 1, 2007; 21(10): 2487 - 2502. [Abstract] [Full Text] [PDF]

				D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]

				C. D. Blundell, D. J. Mahoney, M. R. Cordell, A. Almond, J. D. Kahmann, A. Perczel, J. D. Taylor, I. D. Campbell, and A. J. Day Determining the Molecular Basis for the pH-dependent Interaction between the Link Module of Human TSG-6 and Hyaluronan J. Biol. Chem., April 27, 2007; 282(17): 12976 - 12988. [Abstract] [Full Text] [PDF]

				F. J. Diaz, K. Wigglesworth, and J. J. Eppig Oocytes determine cumulus cell lineage in mouse ovarian follicles J. Cell Sci., April 15, 2007; 120(8): 1330 - 1340. [Abstract] [Full Text] [PDF]

				M. Hsieh, D. Lee, S. Panigone, K. Horner, R. Chen, A. Theologis, D. C. Lee, D. W. Threadgill, and M. Conti Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation Mol. Cell. Biol., March 1, 2007; 27(5): 1914 - 1924. [Abstract] [Full Text] [PDF]

				R. Forteza, S. M. Casalino-Matsuda, M. E. Monzon, E. Fries, M. S. Rugg, C. M. Milner, and A. J. Day TSG-6 Potentiates the Antitissue Kallikrein Activity of Inter-{alpha}-inhibitor through Bikunin Release Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 20 - 31. [Abstract] [Full Text] [PDF]

				M. Shimada, I. Hernandez-Gonzalez, I. Gonzalez-Robanya, and J. S. Richards Induced Expression of Pattern Recognition Receptors in Cumulus Oocyte Complexes: Novel Evidence for Innate Immune-Like Functions during Ovulation Mol. Endocrinol., December 1, 2006; 20(12): 3228 - 3239. [Abstract] [Full Text] [PDF]

				T. Takahashi, J. D. Morrow, H. Wang, and S. K. Dey Cyclooxygenase-2-derived Prostaglandin E2 Directs Oocyte Maturation by Differentially Influencing Multiple Signaling Pathways J. Biol. Chem., December 1, 2006; 281(48): 37117 - 37129. [Abstract] [Full Text] [PDF]

				Y.-Q. Su, M. Nyegaard, M. T. Overgaard, J. Qiao, and L. C. Giudice Participation of Mitogen-Activated Protein Kinase in Luteinizing Hormone-Induced Differential Regulation of Steroidogenesis and Steroidogenic Gene Expression in Mural and Cumulus Granulosa Cells of Mouse Preovulatory Follicles Biol Reprod, December 1, 2006; 75(6): 859 - 867. [Abstract] [Full Text] [PDF]

				I. Hernandez-Gonzalez, I. Gonzalez-Robayna, M. Shimada, C. M. Wayne, S. A. Ochsner, L. White, and J. S. Richards Gene Expression Profiles of Cumulus Cell Oocyte Complexes during Ovulation Reveal Cumulus Cells Express Neuronal and Immune-Related Genes: Does this Expand Their Role in the Ovulation Process? Mol. Endocrinol., June 1, 2006; 20(6): 1300 - 1321. [Abstract] [Full Text] [PDF]

				M. Shimada, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, and J. S. Richards Paracrine and Autocrine Regulation of Epidermal Growth Factor-Like Factors in Cumulus Oocyte Complexes and Granulosa Cells: Key Roles for Prostaglandin Synthase 2 and Progesterone Receptor Mol. Endocrinol., June 1, 2006; 20(6): 1352 - 1365. [Abstract] [Full Text] [PDF]

				W. Selbi, A. J. Day, M. S. Rugg, C. Fulop, C. A. de la Motte, T. Bowen, V. C. Hascall, and A. O. Phillips Overexpression of Hyaluronan Synthase 2 Alters Hyaluronan Distribution and Function in Proximal Tubular Epithelial Cells J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1553 - 1567. [Abstract] [Full Text] [PDF]

				V. Sriraman, M. D. Rudd, S. M. Lohmann, S. M. Mulders, and J. S. Richards Cyclic Guanosine 5'-Monophosphate-Dependent Protein Kinase II Is Induced by Luteinizing Hormone and Progesterone Receptor-Dependent Mechanisms in Granulosa Cells and Cumulus Oocyte Complexes of Ovulating Follicles Mol. Endocrinol., February 1, 2006; 20(2): 348 - 361. [Abstract] [Full Text] [PDF]

				T. Pakarainen, F.-P. Zhang, L. Nurmi, M. Poutanen, and I. Huhtaniemi Knockout of Luteinizing Hormone Receptor Abolishes the Effects of Follicle-Stimulating Hormone on Preovulatory Maturation and Ovulation of Mouse Graafian Follicles Mol. Endocrinol., October 1, 2005; 19(10): 2591 - 2602. [Abstract] [Full Text] [PDF]

				S. A. Kuznetsova, A. J. Day, D. J. Mahoney, M. S. Rugg, D. F. Mosher, and D. D. Roberts The N-terminal Module of Thrombospondin-1 Interacts with the Link Domain of TSG-6 and Enhances Its Covalent Association with the Heavy Chains of Inter-{alpha}-trypsin Inhibitor J. Biol. Chem., September 2, 2005; 280(35): 30899 - 30908. [Abstract] [Full Text] [PDF]

				D. J. Mahoney, B. Mulloy, M. J. Forster, C. D. Blundell, E. Fries, C. M Milner, and A. J. Day Characterization of the Interaction between Tumor Necrosis Factor-stimulated Gene-6 and Heparin: IMPLICATIONS FOR THE INHIBITION OF PLASMIN IN EXTRACELLULAR MATRIX MICROENVIRONMENTS J. Biol. Chem., July 22, 2005; 280(29): 27044 - 27055. [Abstract] [Full Text] [PDF]

				M. S. Rugg, A. C. Willis, D. Mukhopadhyay, V. C. Hascall, E. Fries, C. Fulop, C. M. Milner, and A. J. Day Characterization of Complexes Formed between TSG-6 and Inter-{alpha}-inhibitor That Act as Intermediates in the Covalent Transfer of Heavy Chains onto Hyaluronan J. Biol. Chem., July 8, 2005; 280(27): 25674 - 25686. [Abstract] [Full Text] [PDF]

				J. M. A. Emmen, J. F. Couse, S. A. Elmore, M. M. Yates, G. E. Kissling, and K. S. Korach In Vitro Growth and Ovulation of Follicles from Ovaries of Estrogen Receptor (ER){alpha} and ER{beta} Null Mice Indicate a Role for ER{beta} in Follicular Maturation Endocrinology, June 1, 2005; 146(6): 2817 - 2826. [Abstract] [Full Text] [PDF]

				C. D. Blundell, A. Almond, D. J. Mahoney, P. L. DeAngelis, I. D. Campbell, and A. J. Day Towards a Structure for a TSG-6{middle dot}Hyaluronan Complex by Modeling and NMR Spectroscopy: INSIGHTS INTO OTHER MEMBERS OF THE LINK MODULE SUPERFAMILY J. Biol. Chem., May 6, 2005; 280(18): 18189 - 18201. [Abstract] [Full Text] [PDF]

				J. S. Richards, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, E. Teuling, Y. Lo, D. Boerboom, A. E. Falender, K. H. Doyle, R. G. LeBaron, V. Thompson, et al. Regulated Expression of ADAMTS Family Members in Follicles and Cumulus Oocyte Complexes: Evidence for Specific and Redundant Patterns During Ovulation Biol Reprod, May 1, 2005; 72(5): 1241 - 1255. [Abstract] [Full Text] [PDF]

				K. W. Sanggaard, H. Karring, Z. Valnickova, I. B. Thogersen, and J. J. Enghild The TSG-6 and I{alpha}I Interaction Promotes a Transesterification Cleaving the Protein-Glycosaminoglycan-Protein (PGP) Cross-link J. Biol. Chem., March 25, 2005; 280(12): 11936 - 11942. [Abstract] [Full Text] [PDF]

				M. Shimada, M. Nishibori, Y. Yamashita, J. Ito, T. Mori, and J. S. Richards Down-Regulated Expression of A Disintegrin and Metalloproteinase with Thrombospondin-Like Repeats-1 by Progesterone Receptor Antagonist Is Associated with Impaired Expansion of Porcine Cumulus-Oocyte Complexes Endocrinology, October 1, 2004; 145(10): 4603 - 4614. [Abstract] [Full Text] [PDF]

				Y.-C. Hu, P.-H. Wang, S. Yeh, R.-S. Wang, C. Xie, Q. Xu, X. Zhou, H.-T. Chao, M.-Y. Tsai, and C. Chang Subfertility and defective folliculogenesis in female mice lacking androgen receptor PNAS, August 3, 2004; 101(31): 11209 - 11214. [Abstract] [Full Text] [PDF]

				D. Mukhopadhyay, A. Asari, M. S. Rugg, A. J. Day, and C. Fulop Specificity of the Tumor Necrosis Factor-induced Protein 6-mediated Heavy Chain Transfer from Inter-{alpha}-trypsin Inhibitor to Hyaluronan: IMPLICATIONS FOR THE ASSEMBLY OF THE CUMULUS EXTRACELLULAR MATRIX J. Biol. Chem., March 19, 2004; 279(12): 11119 - 11128. [Abstract] [Full Text] [PDF]