SHAP (serum-derived hyaluronan-associated protein)-HA complexes in the extracellular matrix are the heavy chains of the inter--trypsin inihibitor (ITI) family in serum supplemented to culture medium. The ITI family members are synthesized and assembled in liver and secreted into blood at high concentrations . The members are composed of a common light chain, bikunin (Bik), and one or two of the three genetically different heavy chains (HC1, HC2, and HC3) . Free bikunin in circulation is excreted rapidly into the urine where it is
present as the urinary trypsin inhibitor.
General function
Cell adhesion molecule
Comment
Cellular localization
Extracellular Matrix, Secreted, Plasma membrane
Comment
Ovarian function
Cumulus expansion, Ovulation
Comment
Reproductive failure in mice lacking inter-alpha-trypsin inhibitor (ITI)--ITI target genes in mouse ovary identified by microarray analysis. Suzuki M et al. Bikunin, a Kunitz-type protease inhibitor, is found in blood and urine. It has been established by two laboratories independently that the bikunin knockout female mice display a severe reduction in fertility: the cumulus oophorus has a defect in forming the extracellular hyaluronan-rich matrix during expansion. Proteins of the inter-alpha-trypsin inhibitor (ITI) family are eliminated in mice in which the bikunin gene has been inactivated, since bikunin is essential for their biosynthesis. Proteins of the ITI family may contribute to the microenvironment in which ovulation takes place. It is not clear, however, whether a single mechanism affects the reproductive function including ovulation. For identifying the full repertoire of the ITI deficiency-related genes, a cDNA microarray hybridization screening was conducted using mRNA from ovaries of wild-type or bik(-/-) female mice. A number of genes were identified and their regulation was confirmed by real-time RT-PCR analysis. Our screen identified that 29 (0.7%) and 5 genes (0.1%) of the genes assayed were, respectively, up- and down-regulated twofold or more. The identified genes can be classified into distinct subsets. These include stress-related, apoptosis-related, proteases, signaling molecules, aging-related, cytokines, hyaluronan metabolism and signaling, reactive oxygen species-related, and retinoid metabolism, which have previously been implicated in enhancing follicle development and/or ovulation. Real-time RT-PCR analysis confirmed that these genes were up- and down-regulated two- to tenfold by bikunin knockout. These studies demonstrate that proteins of the ITI family may exert potent regulatory effects on a major physiological reproductive process, ovulation.
Expression regulated by
Comment
Ovarian localization
, Follicular Fluid
Comment
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Zhuo LS, et al 2001 reported that defect in SHAP-hyaluronan complex causes severe female
infertility in mice following inactivation of the bikunin gene.
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 authors 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.