Knockout of Pentraxin 3, a Downstream Target of Growth Differentiation Factor-9, Causes Female Subfertility

Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, United States
Molecular Endocrinology (Impact Factor: 4.02). 07/2002; 16(6):1154-67. DOI: 10.1210/me.16.6.1154
Source: PubMed


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.

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    • "Previously, the expression of TNFAIP6 transcript and protein was detected in porcine oocyte-cumulus complexes (OCCs) [6] [17] [18]. Finally, PTX3 is also important for stabilization of expanded cECM, because Ptx3 null mice are infertile due to the instability of the expanded matrix [14] [15]. "
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    ABSTRACT: This study was designed to determine whether inhibition of either cyclooxygenase-2 (COX-2) by indomethacin or progesterone receptor (PR) by PR antagonist, RU486, affects oocyte maturation, progesterone production and covalent binding between hyaluronan (HA) and heavy chains of inter-alpha trypsin inhibitor (IαI) as well as expression of cumulus expansion-associated proteins (HABP, TNFAIP6, PTX3) in oocyte-cumulus complexes (OCC). The experiments were based on freshly isolated porcine OCC cultures in which the consequences of PR and COX-2 inhibition on the final processes of oocyte maturation were determined. Granulosa cells (GCs) and OCC were cultured in medium supplemented with FSH/LH (both 100 ng/mL) in the presence/absence of RU486 or indomethacin. Western blot analysis, 3H-glucosamine hydrochloride assay, immunofluorescence and radioimmunoassay were performed. Only treatment with RU486 (25 μM) caused a decrease in the number of oocytes reaching germinal vesicle breakdown (GVBD) and metaphase II (M II) stage compared with indomethacin (100 μM) or FSH/LH treatment alone after 44 h. All treated OCC synthesized an almost equal amount of HA. Heavy chains (of IαI)-HA covalent complexes were formed during in vitro FSH/LH-stimulated expansion in RU486- or indomethacin-treated OCC. FSH/LH-induced progesterone production by OCC was increased in the presence of RU486 after 44 h. In contrast, a decrease of FSH/LH-stimulated progesterone production by GCs was detected in the presence of either RU486 or indomethacin after 72 h. We suggest that the PR-dependent pathway may be involved in the regulation of oocyte maturation. Both PR and COX-2 regulate FSH/LH-stimulated progesterone production by OCC and GCs.
    Domestic Animal Endocrinology 07/2014; 48(1). DOI:10.1016/j.domaniend.2014.01.003 · 2.17 Impact Factor
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    • "Normal expansion requires the expression of several transcripts encoding HAS2, PTGS2, PTX3 and TNFAIP6 (Davis et al. 1999; Varani et al. 2002; Fulop et al. 2003; Ochsner et al. 2003; Sugiura et al. 2009). Cumulus expansion is induced by an LH surge the signal of which within the follicles is mediated by epidermal growth factor (EGF)-like peptides produced by granulosa cells (Park et al. 2004; Shimada et al. 2006). "
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    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; 85(6). DOI:10.1111/asj.12200 · 0.96 Impact Factor
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    • "TSG6 binding cross-links ITI heavy chains to hyaluronic acid (Fulop et al., 2003; Mukhopadhyay et al., 2004). Pentraxin 3 (PTX3), is also secreted by cumulus cells and acts to stabilize TNFAIP6 protein to maintain the expanded matrix (Salustri et al., 2004; Varani et al., 2002). In addition to extracellular matrix, intracellular signaling cascades play crucial roles in controlling by gonadotropins and growth factors-induced cumulus expansion. "
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    ABSTRACT: This study was conducted to investigate the effects of Trichostatin A (TSA) on cumulus expansion during mouse oocyte maturation. TSA treatment inhibited cumulus expansion and significantly reduced the cumulus expansion index (CEI) (p<0.05). To determine the underlying mechanism, the expression levels of several key factors that play crucial roles in cumulus expansion including components of extracellular matrix (ECM) (Has2, Ptgs2, Ptx3, and Tnfaip6) and Growth differentiation factor 9 (GDF9) were measured in control and TSA treated samples by real-time PCR. The effect of TSA on ERK phosphorylation (p-ERK1/2) in cumulus cells and GDF9 protein level in fully grown oocytes (FGOs) were detected by Western blotting. The expression levels of the ECM genes were significantly decreased (p<0.05) by TSA treatment while GDF9 expression did not response to TSA (p>0.05). TSA treatment blocked the activation of ERK1/2 (p<0.05) and had no significant effect on GDF9 protein expression (p>0.05). Collectively, these results suggested that TSA treatment altered ECM gene expression and blocked ERK1/2 activation to inhibit cumulus expansion in the mouse.
    Asian Australasian Journal of Animal Sciences 11/2013; 26(11):1545-52. DOI:10.5713/ajas.2013.13128 · 0.54 Impact Factor
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