Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility.

Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Molecular Endocrinology (Impact Factor: 4.75). 07/2002; 16(6):1154-67. DOI: 10.1210/me.16.6.1154
Source: PubMed

ABSTRACT The ovulatory process is tightly regulated by endocrine as well as paracrine factors. In the periovulatory period, extensive remodeling of the follicle wall occurs to allow the extrusion of the oocyte and accompanying cumulus granulosa cells. Growth differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) are secreted members of the TGFbeta superfamily that are expressed beginning in the oocyte of small primary follicles and through ovulation. Besides its critical role as a growth and differentiation factor during early folliculogenesis, GDF-9 also acts as a paracrine factor to regulate several key events in preovulatory follicles. By analyzing GDF-9-regulated expression profiles using gene chip technology, we identified TNF-induced protein 6 (Tnfip6) and pentraxin 3 (Ptx3 or PTX3) as novel factors induced by GDF-9 in granulosa cells of preovulatory follicles. Whereas Tnfip6 is induced in all granulosa cells by the LH surge, Ptx3 expression in the ovary is specifically observed after the LH surge in the cumulus granulosa cells adjacent to the oocyte. PTX3 is a member of the pentraxin family of secreted proteins, induced in several tissues by inflammatory signals. To define PTX3 function during ovulation, we generated knockout mice lacking the Ptx3 gene. Homozygous null (Ptx3(-/-)) mice develop normally and do not show any gross abnormalities. Whereas Ptx3(-/-) males are fertile, Ptx3(-/-) females are subfertile due to defects in the integrity of the cumulus cell-oocyte complex that are reminiscent of Bmp15(-/-)Gdf9(+/-) double mutant and BMP type IB receptor mutant mice. These studies demonstrate that PTX3 plays important roles in cumulus cell-oocyte interaction in the periovulatory period as a downstream protein in the GDF-9 signal transduction cascade.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are members of the transforming growth factor-β (TGF-β) family, and their roles in oocyte maturation and cumulus expansion are well known in the mouse and human, but not in the pig. We investigated GDF9 and BMP15 expressions in porcine oocytes during in vitro maturation. A significant increase in the mRNA levels of GDF9 and BMP15 was observed at germinal vesicle breakdown, with expression levels peaking at metaphase I (MI), but decreasing at metaphase II (MII). GDF9 and BMP15 protein localized to the oocyte cytoplasm. While treatment with GDF9 and BMP15 increased the expression of genes involved in both oocyte maturation (c-mos, cyclinb1 and cdc2) and cumulus expansion (has2, ptgs2, ptx3 and tnfaip6), SB431542 (a TGFβ-GDF9 inhibitor) decreased meiotic maturation at MII. Following parthenogenetic activation, the percentage of blastocysts in SB431542 treatment was lower than in the control (41.3% and 74.4%, respectively). Treatment with GDF9 and BMP15 also increased the mRNA levels of maternal genes such as c-mos [a regulatory subunit of mitogen-activated protein kinase (MAPK)], and cyclinb1 and cdc2 [regulatory subunits of maturation/M-phase-promoting factor (MPF)]; however, SB431542 significantly decreased their mRNA levels. These data were supported by poly (A)-test PCR and protein activity analyses. Our results show that GDF9 and BMP15 participate in cumulus expansion and that they stimulate MPF and MAPK activities in porcine oocytes during in vitro maturation.
    Reproduction in Domestic Animals 12/2013; · 1.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian oocytes secrete transforming growth factor β (TGF-β) superfamily proteins, such as growth differentiation factor 9 (GDF9), bone morphogenetic protein 6 (BMP6) and BMP15, and fibroblast growth factors (FGFs). These oocyte-derived paracrine factors (ODPFs) play essential roles in regulating the differentiation and function of somatic granulosa cells as well as the development of ovarian follicles. In addition to the importance of individual ODPFs, emerging evidence suggests that the interaction of ODPF signals with other intra-follicular signals, such as estrogen, is critical for folliculogenesis. In this review, we will discuss the current understanding of the role of ODPFs in follicular development with an emphasis on their interaction with estrogen signaling in regulation of the differentiation and function of granulosa cells.
    Animal Science Journal 04/2014; · 1.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pentraxin-3 (PTX-3), like C-reactive protein (CRP), is an acute phase protein belonging to the pentraxin superfamily. Moreover, it is expressed in the cumulus oophorus and appears to be involved in female fertility. Aim of the study was to assess whether PTX-3 levels are altered in PCOS women and which relationships do they show with the main features of these subjects. Cross-sectional study, conducted at the outpatient clinic of an academic center. Sixty-six women affected with PCOS and 51 healthy controls were studied. Plasma PTX-3 and serum CRP were measured by ELISA. Androgens were measured by liquid chromatography mass spectrometry and free testosterone by equilibrium dialysis. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique. Adjusting for age and BMI, plasma PTX-3 was reduced in PCOS women (p=0.036), in contrast with serum CRP which was increased (p=0.004). In multiple regression analysis serum androgens and other endocrine and ovarian features of PCOS were predictors of PTX-3 levels, whereas body fat was the main independent predictor of CRP concentrations. Plasma PTX-3 levels are reduced in PCOS women and independently associated with hyperandrogenism and other endocrine and ovarian features of PCOS.
    European Journal of Endocrinology 12/2013; · 3.14 Impact Factor