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doi: 10.1242/10.1242/dev.00422
DEVELOPMENT AND DISEASE |
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-
-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--trypsin inhibitor, Hyaluronan, Extracellular matrix, Infertility
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