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

Csaba Fülöp, Sándor Szántó, Durba Mukhopadhyay, Tamás Bárdos, Rajesh V. Kamath, Marylin S. Rugg, Anthony J. Day, Antonietta Salustri, Vincent C. Hascall, Tibor T. Glant, Katalin Mikecz

Research output: Contribution to journalArticle

290 Citations (Scopus)

Abstract

Mucification of the cumulus layer around the oocyte is an oligatory 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-α-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.

Original languageEnglish
Pages (from-to)2253-2261
Number of pages9
JournalDevelopment
Volume130
Issue number10
DOIs
Publication statusPublished - May 1 2003

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Keywords

  • Cumulus cell
  • Extracellular matrix
  • Hyaluronan
  • Infertility
  • Inter-α-trypsin inhibitor
  • Tnfip6
  • Tsg6
  • Tumor necrosis factor-induced protein-6

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Fülöp, C., Szántó, S., Mukhopadhyay, D., Bárdos, T., Kamath, R. V., Rugg, M. S., Day, A. J., Salustri, A., Hascall, V. C., Glant, T. T., & Mikecz, K. (2003). Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice. Development, 130(10), 2253-2261. https://doi.org/10.1242/dev.00422