Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice.
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.
Fülöp
Csaba
C
Section of Connective Tissue Biology, Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. fulop@bme.ri.ccf.org
Szántó
Sándor
S
Mukhopadhyay
Durba
D
Bárdos
Tamás
T
Kamath
Rajesh V
RV
Rugg
Marylin S
MS
Day
Anthony J
AJ
Salustri
Antonietta
A
Hascall
Vincent C
VC
Glant
Tibor T
TT
Mikecz
Katalin
K
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D007247:Infertility, Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000502:physiology*; D010053:Ovary / Q000033:anatomy & histology / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D015815:Cell Adhesion Molecules; D011994:Recombinant Proteins; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse; D006820:Hyaluronic Acid