Defect in SHAP-hyaluronan complex causes severe female infertility. A study by inactivation of the bikunin gene in mice.
Hyaluronan (HA) associates with proteins and proteoglycans to form the extracellular HA-rich matrices that significantly affect cellular behaviors. So far, only the heavy chains of the plasma inter-alpha-trypsin inhibitor (ITI) family, designated as SHAPs (serum-derived hyaluronan-associated proteins), have been shown to bind covalently to HA. The physiological significance of such a unique covalent complex has been unknown but is of great interest, because HA and the ITI family are abundant in tissues and in plasma, respectively, and the SHAP-HA complex is formed wherever HA meets plasma. We abolished the formation of the SHAP-HA complex in mice by targeting the gene of bikunin, the light chain of the ITI family members, which is essential for their biosynthesis. As a consequence, the cumulus oophorus, an investing structure unique to the oocyte of higher mammals, had a defect in forming the extracellular HA-rich matrix during expansion. The ovulated oocytes were completely devoid of matrix and were unfertilized, leading to severe female infertility. Intraperitoneal administration of ITI, accompanied by the formation of the SHAP-HA complex, fully rescued the defects. We conclude that the SHAP-HA complex is a major component of the HA-rich matrix of the cumulus oophorus and is essential for fertilization in vivo.
Zhuo
L
L
Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.
Yoneda
M
M
Zhao
M
M
Yingsung
W
W
Yoshida
N
N
Kitagawa
Y
Y
Kawamura
K
K
Suzuki
T
T
Kimata
K
K
D000510:Alpha-Globulins / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005260:Female; D006820:Hyaluronic Acid / Q000502:physiology*; D007247:Infertility, Female / Q000209:etiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D014360:Trypsin Inhibitor, Kunitz Soybean
D000510:Alpha-Globulins; D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; C011877:inter-alpha-inhibitor; D006820:Hyaluronic Acid; D014360:Trypsin Inhibitor, Kunitz Soybean