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doi: 10.1242/10.1242/dev.00422


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Development 130, 2253-2261 (2003)
Copyright © 2003 The Company of Biologists Limited


DEVELOPMENT AND DISEASE

Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice

Csaba Fülöp1,*, Sándor Szántó2, Durba Mukhopadhyay1, Tamás Bárdos2, Rajesh V. Kamath2, Marylin S. Rugg3, Anthony J. Day3, Antonietta Salustri4, Vincent C. Hascall1, Tibor T. Glant2 and Katalin Mikecz2

1 Section of Connective Tissue Biology, Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
2 Section of Biochemistry and Molecular Biology, Departments of Orthopedic Surgery and Biochemistry, Rush University at Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA
3 MRC, Immunochemistry Unit, Department of Biochemistry, University of Oxford, OX1 3QU Oxford, UK
4 Department of Public Health and Cell Biology, University of Rome `Tor Vergata', 00133 Rome, Italy

* Author for correspondence (e-mail: fulop{at}bme.ri.ccf.org)

Accepted 23 January 2003

Mucification of the cumulus layer around the oocyte is an obligatory process for female fertility. Tumor necrosis factor-induced protein-6 (TNFIP6 or TSG6) has been shown to be specifically expressed during this process. We have generated TNFIP6-deficient mice and tested the ability of their cumulus cells to undergo mucification. Cumulus cell-oocyte complexes fail to expand in TNFIP6-deficient female mice because of the inability of the cumulus cells to assemble their hyaluronan-rich extracellular matrix. The impaired cumulus matrix formation is due to the lack of covalent complexes between hyaluronan and the heavy chains of the inter-{alpha}-trypsin inhibitor family. As a consequence, TNFIP6-deficient females are sterile. Cultured TNFIP6-deficient cumulus cell-oocyte complexes also fail to expand when stimulated with dibutyryl cyclic AMP or epidermal growth factor. Recombinant TNFIP6 is able to catalyze the covalent transfer of heavy chains to hyaluronan in a cell-free system, restore the expansion of Tnfip6-null cumulus cell-oocyte complexes in vitro, and rescue the fertility in Tnfip6-null females. These results provide clear evidence that TNFIP6 is a key catalyst in the formation of the cumulus extracellular matrix and indispensable for female fertility.

Key words: Cumulus cell, Tumor necrosis factor-induced protein-6, Tnfip6, Tsg6, Inter-{alpha}-trypsin inhibitor, Hyaluronan, Extracellular matrix, Infertility




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