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Department of Pathology (S.V., J.A.E., C.Y., M.M.M.), Department of Molecular and Cellular Biology (J.D., F.J.D., M.M.M.), Department of Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; and Wyeth Research (H.F.H., M.C.B.), Cambridge, Massachusetts 02140
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., The Stuart A. Wallace Chair and Professor, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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There is increasing evidence that the oocyte plays an active role in cumulus expansion (for review see Ref. 4); a factor secreted from the oocyte has been shown to induce cumulus expansion through increased hyaluronic acid matrix synthesis. Growth differentiation factor-9 (GDF-9 or Gdf9), an oocyte-secreted member of the TGF-ß superfamily, is expressed in growing oocytes throughout all stages of folliculogenesis and in cumulus cell-oocyte complexes after ovulation (5, 6, 7). Knockout of the Gdf9 gene leads to infertility due to a block at the primary follicle stage, absence of thecal layer formation, and defects in oocyte meiotic competence (8, 9, 10). In vitro, recombinant GDF-9 can substitute for the oocyte in inducing cumulus expansion and regulates the expression of several genes important for ovulation in preovulatory granulosa cells (6). Recombinant GDF-9 induces hyaluronic acid synthase 2 (6), the cumulus granulosa cell enzyme responsible for hyaluronic acid deposition (11), cyclooxygenase 2 (COX2 or prostaglandin endoperoxide synthase 2), the prostaglandin pathway enzyme expressed in granulosa cells of the preovulatory follicle after the LH surge (10, 12), and the PGE2 receptor, EP2 [PTGEREP2; (13)]. Cox2 knockout mice are infertile and demonstrate reduced ovulation and fertilization rates. Similarly, EP2 receptor knockout mice show reduced female fertility due to a decreased rate of in vivo fertilization and defects in cumulus expansion (14, 15, 16). Consistent with the recombinant GDF-9 studies, Bmp15-/- Gdf9+/- double mutant female mice are subfertile due to defects in ovulation and the integrity of the cumulus-oocyte complexes (i.e. the cumulus cells are not adherent to the oocyte after ovulation) (17). Thus, in vitro and in vivo, GDF-9 regulates the expression of cumulus cell proteins that play key functions in the periovulatory period.
To identify additional genes that are regulated by GDF-9 in preovulatory granulosa cells and play roles at this stage of folliculogenesis, we used Affymetrix (Santa Clara, CA) gene chip technology. In addition to confirming Cox2 and Has2 (hyaluron synthase 2) as genes downstream of GDF-9, we identified TNF-induced protein 6 (Tnif6) and pentraxin 3 (Ptx3 or PTX3) as novel genes induced by GDF-9 in the periovulatory granulosa cells of the ovary. PTX3 is a secreted protein belonging to the long pentraxin family of inflammatory proteins, named after the characteristic discoid arrangement of the five noncovalently bound subunits (18). Because the physiological roles of PTX3 in cumulus cell physiology and ovulation were unknown, we generated a Ptx3 knockout mouse model. Ptx3 knockout mice are subfertile secondary to ovulatory and cumulus cell-oocyte defects.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) confirmed our previous data (6, 13) that GDF-9 regulates the synthesis of several important ovarian gene products in the preovulatory follicle including Cox2, which encodes the enzyme responsible for prostaglandin synthesis in cumulus granulosa cells, and Has2, expressed in cumulus cell-oocyte complexes and involved in cumulus expansion. Ovaries from Gdf9 knockout females demonstrate a decrease in the levels of follistatin, Igf1, and inhibin/activin ßB mRNAs but show no difference in the levels of inhibin 
mRNA (10). In the gene chip experiment, GDF-9 appears to positively regulate the synthesis of follistatin, IGF-I, and inhibin/activin ßB mRNAs. As a control, expression of inhibin , one of the most abundant ovarian mRNAs, is unchanged in the presence or absence of GDF-9. These findings were confirmed by Northern blot analysis (fold change presented in Table 1).
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). Our Northern blot results of Tnfip6 were more consistent with the 11K ChipB results because Tnfip6 was significantly increased in the absence of GDF-9 (compared with freshly isolated granulosa cells), and the presence of GDF-9 resulted in a 5.6-fold up-regulation of Tnfip6 mRNA (Fig. 1A). In addition, Tnfip6 was absent in Gdf9 knockout ovaries, detectable at low levels in adult wild-type ovaries, and up-regulated by PMSG (48 h) and human CG (hCG) (5 h) treatment of immature mice (Fig. 1B). These findings suggest that GDF-9 and other factors may regulate Tnfip6 synthesis in the mammalian ovary. Similar analyses of Ptx3 expression were performed. In two independent series of experiments, Ptx3 was assigned "absent" (4 and 5 mRNA copies/100,000 total mRNA copies) in cells incubated in the absence of GDF-9 but "present" (206 and 146 mRNA copies/100,000 total mRNA copies) in cells treated with GDF-9, thereby showing an average 35.2-fold induction by GDF-9 (Table 1). Northern blot analysis confirmed these findings, demonstrating that Ptx3 is up-regulated 34.8-fold in RNA samples derived from GDF-9-treated granulosa cells (Fig. 1C) compared with RNA from granulosa cells incubated in the absence of GDF-9 (control) or freshly isolated granulosa cells (at time 0). Similar to control granulosa cells, Ptx3 mRNA is undetectable in adult ovaries from Gdf9 knockout mice and barely detectable in adult ovaries from wild-type mice. Similar to Tnfip6, Ptx3 is dramatically up-regulated in ovaries from mice superovulated with PMSG for 48 h and hCG for 5 h (Fig. 1D).
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, A and B, and Fig. 3, A and B). By 5 h after hCG injection, an intense Ptx3 mRNA signal in the cumulus granulosa cells was found, and a few mural granulosa cells that line the antral cavity also express Ptx3 (Fig. 2, C–F). At this time point, Tnfip6 mRNA was detected in all granulosa cells in antral follicles (Fig. 3, C–F). By 12 h after hCG injection, expression of both Ptx3 and Tnfip6 decreased. Ptx3 was no longer seen in mural granulosa cells, but persisted in the cumulus granulosa cells of some cumulus-oocyte complexes (Fig. 2, G and H). Tnfip6 was localized to expanded cumulus cells, with lower levels of expression detected in mural granulosa cells (Fig. 3, G and H). Interestingly, the spatiotemporal expression of Ptx3 is nearly identical to the pattern of Cox2 (10, 12) and Has2 (11), which are also induced in cumulus cells after the LH surge and are up-regulated by GDF-9 in preovulatory granulosa cells in vitro (6, 13). Thus, the findings that Ptx3 is expressed after the LH surge in granulosa cells in closest proximity to the oocyte and also induced in granulosa cells in vitro in response to GDF-9 suggest that the Ptx3 gene is a physiological downstream target of GDF-9.
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, A and B). Surprisingly, after hormonal treatment (PMSG and hCG) and LPS injection, Ptx3 was also detected in the bursa, the epithelial layer that surrounds the ovary, and in adipose tissue connected to the ovary (Fig. 4, C and D). Ovaries from females injected with PMSG and saline show low levels of Ptx3 signal in granulosa cells of antral follicles (Fig. 4, E and F), whereas PMSG injection followed 48 h later by LPS injection (Fig. 4, G and H) induce a low level of expression of Ptx3 mRNA in the stroma of the ovary as well as high levels in the bursa and adipose tissue. The mice injected with LPS showed clear signs of an ongoing acute phase response (i.e. ruffled fur and trembling). Northern blot analysis of RNA from the hearts of injected mice confirmed that the LPS had induced Ptx3 mRNA in extrahepatic sites (data not shown). Thus, these findings suggest that LPS has no direct effects on the ovarian follicle and mainly regulated Ptx3 in the surrounding bursa and adipose tissue.
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). Homologous recombination of the targeting vector at the Ptx3 locus was predicted to yield a null mutation because exon 1 encodes the initiation methionine codon as well as the signal peptide that is required for protein secretion. The Ptx3 targeting vector was electroporated into AB2.2 ES cells, and 29 of 95 (30%) of the ES cell clones analyzed were targeted at the Ptx3 locus. Three of these cell lines were used to produce chimeric male mice that were fertile and transmitted the Ptx3 mutant allele (Ptx3tm1Zuk; herein called Ptx3-) to the F1 progeny. Intercrossing of the F1 heterozygotes yielded F2 progeny including 91 wild-type mice (24.9%), 172 heterozygous (Ptx3+/-) mice (47.2%), and 102 homozygous (Ptx3-/-) mice (27.9%) out of 48 litters analyzed. Thus, the mutated allele is transmitted with the expected Mendelian frequency of 1:2:1, and the male:female ratio is approximately 50:50 (Fig. 5B, top). Southern blot analysis using a probe spanning exons 1 and 2 demonstrated a lack of hybridization in the DNA derived from Ptx3-/- mice, thereby confirming that the mutated allele that we generated is null (Fig. 5B, bottom).
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). Breeding of 129 inbred Ptx3-/- females (n = 3) over a 6-month period failed to produce any offspring in contrast to 129 inbred Ptx3-/- females (n = 7), which yielded 32 litters (0.76 ± 0.1 litters/month) with an average litter size of 5.69 ± 0.33. Thus, Ptx3 plays an important role in female fertility.
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, A and B). The ovulatory function of Ptx3-/- mice was then assayed by determining the ovarian response to superovulation with exogenous gonadotropins. Nineteen to 20 h hours after hormonal (hCG) stimulation, oocytes were recovered from the ampulla of the oviduct. Fewer oocytes were released by Ptx3-/- females (9.9 ± 0.5) compared with Ptx3+/- (31.2 ± 0.6) or wild-type females (22.2 ± 0.9) [P < 0.001]. Histological analysis of the mutant ovaries in these experiments indicated that the presence of oocytes in luteinized follicles is a rare event (Fig. 6C) and does not account for the reduction in the number of eggs released into the oviduct. Surprisingly, oocytes isolated from Ptx3-/- females were denuded of cumulus granulosa cells (Fig. 7B), whereas oocytes released from Ptx3+/- (Fig. 7A) and wild-type females (data not shown) retained the cumulus cells, which form a compact 3-dimensional mucoelastic structure surrounding the oocyte.
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) similar to Ptx3+/- controls. However, in several preovulatory follicles, the oocyte is not surrounded by cumulus cells (Fig. 6E) or the expanded cumulus mass appears to be randomly scattered around the oocyte (Fig. 6F).
Several reports indicate that the cumulus mass that accompanies the ovulating oocyte into the oviduct plays a critical role in successful fertilization of the released ovum (3, 15, 21, 22). To determine the fertilization rate in Ptx3-/- mice, we superovulated 3-wk-old females and mated them to stud males. Approximately 20 h after the hCG injection, we isolated oocytes and one-cell embryos from the ampulla of the oviduct. Fifty-five percent of the oocytes from Ptx3+/- females successfully developed into two-cell embryos after 24 h of culture (Table 3). In contrast, only 1.3% of the oocytes from Ptx3-/- female mice developed to the two-cell stage, demonstrating a dramatic reduction in fertilization rate in the absence of PTX3. Thus, defects in cumulus cell adherence to the oocyte in the periovulatory period reduce the ovulation and fertilization rates, resulting in subfertility of the Ptx3-/- female mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the periovulatory period, the oocyte secretes one or more factors that affect the surrounding cumulus cells (4). Our laboratory has presented data that the oocyte-secreted protein GDF-9 stimulates hyaluronan synthase 2, cyclooxygenase 2, and the EP2 PGE2 receptor mRNA and inhibits urokinase plasminogen activator and LH receptor mRNA in preovulatory granulosa cells (10, 13). Thus, GDF-9 appears to be a key oocyte-secreted regulator of cumulus cell gene expression and cumulus cell function in the periovulatory period. In this study, we also show that Tnfip6 and Ptx3 are two additional genes, which are regulated by GDF-9 in our granulosa cell expression system. Both of these proteins appear to be integral factors in the cumulus cell-oocyte complex after the LH surge (see below).
After the LH surge, the cumulus cells of the preovulatory follicle lose contact with each other and the oocyte. However, the cumulus cells and oocyte are embedded in a mucoelastic extracellular matrix (23) rich in hyaluronic acid, the product of HAS2 from the cumulus cells (11). The matrix contains a number of proteins which stabilize the hyaluronic acid matrix. The hyaluronic acid surface receptor, CD44, appears to anchor the matrix to the cumulus cells (24). Multiple proteoglycans, which bind hyaluronic acid, are also present in the cumulus cell secreted matrix (25). The hyaluronic acid chains are held together by various cumulus cell-derived and serum-derived link proteins. In vitro, newly synthesized hyaluronic acid chains are retained in the cumulus cell-oocyte complex only if serum is present. In particular, serum contains inter--trypsin inhibitor (ITI), a complex of bikunin (called urinary trypsin inhibitor) and one or two heavy chains (HC1, HC2, or HC3) linked through a chondroitin-4-sulfate chain of bikunin (23). After the LH surge, the blood-follicle barrier is open to ITI, and the heavy chains of ITI are transferred to the cumulus cellproduced hyaluronic acid to form a covalent complex. The complex appears to be strengthened further by TNFIP6, a hyaluronic acid binding protein that is covalently attached to an ITI heavy chain and strongly interacts with hyaluronic acid (26).
Knockout models lacking several of the above factors have demonstrated that cumulus expansion and the integrity of the hyaluronic acid-rich matrix are critical for female fertility. Cumulus cell-oocyte complexes from mice lacking cyclooxygenase 2 (27) and the EP2 PGE2 receptor (15) fail to demonstrate cumulus expansion. Preovulatory follicles from bikunin knockout mice demonstrate disorganized cumulus cell-oocyte complexes resulting in dramatically reduced fertility (28, 29). Although a viable knockout of Tnfip6 has not yet been reported, our studies here suggest that the oocyte, and specifically GDF-9 from the oocyte, plays a critical role in the induction of Tnfip6 from the cumulus cells of periovulatory follicles and that this oocyte regulation of Tnfip6 is not activated until after the LH surge in mice (our studies here and Ref. 26) and rats (30). In addition, nonoocyte factors must play a role in Tnfip6 induction because the gene is also expressed in the mural granulosa cells.
What function does PTX3 play in this process? Ovaries and cumulus cell-oocyte complexes within the Ptx3 knockout ovaries appear relatively intact before the breakdown of the follicle wall. Because periovulatory action of GDF-9 induces the synthesis of other components of the cumulus cell-oocyte extracellular matrix, our findings that GDF-9 induces the secreted protein PTX3 in the same time period suggests that PTX3 also becomes part of this extracellular matrix. In the mouse, Ptx3 is induced in cells and at other sites by proinflammatory signals such as IL-1 and TNF as well as LPS. PTX3 has been characterized as a marker of human inflammatory conditions such as septic shock (31), rheumatoid arthritis (32), Castleman’s disease (33), and acute myocardial infarction (34). A protective role of PTX3 at these sites could be hypothesized based on the findings that PTX3 binds apoptotic cells in the endothelium, thereby reducing their clearance by antigen-presenting dendritic cells and preventing the eventual onset of an autoimmune reaction (35). Mice overexpressing the Ptx3 gene under its own promoter have improved survival in response to endotoxic shock and sepsis (36), and Ptx3-/- mice have been reported to undergo more severe seizure-related neuronal damage (37). Our findings of reduced ovulation and defects in cumulus cell-oocyte integrity suggest that PTX3 functions to bind to the cumulus cell-oocyte extracellular matrix to protect the oocyte and extracellular matrix from proteolytic enzymes present at the apex of the follicle during the extrusion from the ovary and in the oviductal environment. Proteolytic degradation of the extracellular matrix is a physiological process that starts after ovulation, leading to progressive oocyte denudation that correlates with a decline in the ability of the oocyte to be fertilized (38, 39). Proteases produced by the preovulatory follicle and present in the oviductal environment have been reported to destabilize the cumulus matrix by degrading proteins required for hyaluronan stabilization (40). An untimely release of proteases, as well as a lack of antiprotease activity in the extracellular matrix (e.g. absence of PTX3), might account for early oocyte denudation. Thus, PTX3 appears to protect the cumulus mass that is vital for the capture of the oocyte by the oviductal fimbria and its efficient entry into the oviduct (41, 42). An alternative explanation for the decrease in ovulation in the Ptx3-/- knockout mice is that PTX3 on the surface of the cumulus cell-oocyte complex acts to directly bind the complex to the fimbria of the oviduct to shuttle the complex into the oviduct.
The cumulus mass has previously been shown to play a role in fertilization, facilitating egg-sperm interactions and the subsequent acrosomal reaction (3, 15). Because the cumulus mass surrounding the oocytes of Ptx3-/- mice is disrupted, this is the likely (indirect) cause for their reduced fertilization. Thus, the oocytes in Ptx3-/- mice appear to lose their optimal extracellular environment and show a lower efficiency of ovulation and fertilization.
Our in vitro studies demonstrate that GDF-9 stimulates cumulus expansion of oocytectomized complexes and can regulate 7 genes that are differentially expressed in cumulus granulosa cells (Has2, Cox2, EP2 receptor, Ptx3, and Tnfip6) vs. mural granulosa cells (urokinase plasminogen activator and LH receptor) in the periovulatory follicle (Refs. 6, 13 , and the present studies). Interestingly, the LH surge is the trigger for this differential expression pattern but must do so indirectly because LH receptors are not present on cumulus granulosa cells. This suggests that a factor from the mural granulosa cells or the serum, upon stimulation from LH, positively induces a GDF-9 signal transduction cascade. This could be accomplished by 1) processing of an inactive GDF-9 precursor that is bound to the cumulus cell extracellular matrix or present in the oocytes; 2) stimulating the degradation of an inhibitory protein or complex; 3) up-regulation of a cumulus cell receptor or cytoplasmic cascade; or 4) inducing a transcriptional cofactor, which acts along with GDF-9 regulated transcription factors. Interestingly, mice lacking the type I BMP receptor also have defects in the integrity of cumulus cell-oocyte complexes and have fertility defects but display up-regulated Cox2 mRNA levels (43). Our recent studies have shown that the knockout of the Bmp15 gene, which encodes a member of the TGFß superfamily closely related to Gdf9, results in reduced female fertility. The Bmp15-/- phenotype is exacerbated when the mice also carry a mutation in one of the Gdf9 alleles (i.e. Bmp15-/-Gdf9+/-). Oocytes recovered from these double or single mutant mice are also denuded of cumulus cells, thereby phenocopying the postovulatory defects in the Ptx3-/- mice. Although we do not know whether BMP-15 plays a role in the regulation of Ptx3 gene expression, clearly both GDF-9 and BMP-15 appear to play important roles in the periovulatory ovary. The identification of the receptors involved in GDF-9 and BMP-15 or GDF-9:BMP-15 heterodimer signaling and the possible roles of type I BMP receptor in these pathways (positive or negative) and the regulation of PTX3 and COX2, will require further studies.
In conclusion, we have identified PTX3 as a novel protein downstream of the GDF-9 signal transduction cascade in the preovulatory follicle. Using knockout technology, we demonstrate that PTX3 play key roles in the efficient delivery of the cumulus-oocyte complex to the oviduct and successful fertilization of the egg. These studies further confirm important roles of the cumulus cells and oocyte-somatic cell communication in reproductive physiology.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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RNA Isolation, Granulosa Cell Culture, and Northern Blot Analysis
Mural granulosa cells were isolated from large antral follicles of CD1 mice treated with PMSG for 48 h and placed into culture. The experimental groups were freshly isolated granulosa cells (time 0), cells cultured for 5 h in presence of CHO cell conditioned media containing 50 ng/ml recombinant GDF-9, and cell cultured for the same amount of time with CHO cell conditioned media lacking GDF-9. Total RNA was isolated and used for oligonucleotide array hybridization. RNA isolation and Northern blot analysis were performed as previously described (6). The recombinant GDF-9 medium and the CHO control medium lacking GDF-9 were produced under the same conditions as described previously in the presence of heparin (6). Similar induction of Ptx3 and Cox2 gene expression is observed in the presence of GDF-9containing conditioned medium containing 1% FCS and the absence of heparin (Jorgez, C., and M. M. Matzuk, unpublished data).
ES Cell Manipulation and Southern Blot Analysis
About 15 kb of genomic sequence encompassing the mouse Ptx3 gene was isolated from a 129/SvEv genomic library. This genomic sequence was used to generate a targeting vector to mutate the Ptx3 gene in ES cells. The targeting vector contained 5.8 kb of genomic DNA upstream of Ptx3 exon 1, a selectable marker [the phosphoglycerate kinase promoter, hypoxanthine-guanine phosphoribosyl transferase minigene (PGKhprt) expression cassette], 2 kb of Ptx3 intron 2, and a negative selectable marker (the MC1tk expression cassette) (Fig. 3A). The linearized vector was electroporated into the hprt-negative AB2.2 ES cell line, clones were selected in hypoxantine, aminopteridine, thimidine, and 1-(2'-deoxy-2'fluoro-ß-D-arabinofuranosyl)-5-iodouracil], and DNA from the clones analyzed by Southern blot as described (45, 46, 47). Targeted ES cell clones were injected into blastocysts, as described (46). Thirty percent of the ES cells were targeted at the Ptx3 locus, and three of these ES cell clones (Ptx3-134-A5, Ptx3-134-B2, Ptx3-134-D4) were injected into mouse blastocysts. Male chimeras derived from all three targeted ES cell clones transmitted the mutant Ptx3 allele to F1 offspring. F1 heterozygous mice were intercrossed to produce Ptx3-/- mice. Chimeras were mated to either C57BL6/J females to produce 129/SvEv/C57BL6/J hybrid mice or to 129/SvEv females to produce 129/SvEv inbred mice. Southern blot analysis was used for genotype analysis of all Ptx3 mutant offspring as shown (Fig. 3B).
Superovulation and Isolation of Oocytes/Embryos
Twenty-two to 25-d-old Ptx3+/- and Ptx3-/- female mice were injected with PMSG (ip, 7.5 IU/mouse), and given hCG (ip, 5 IU/mouse) 48 h later. Mice were then either caged overnight or bred to C57/129 hybrid stud males. The following morning eggs and/or embryos were recovered in M2 medium, counted, and cultured in vitro for 24 h in M16 medium.
Statistical Analysis
When appropriate, statistical significance was calculated by one-way ANOVA. Data are expressed as average ± SEM.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: BMF-15, Bone morphogenetic protein-15; COX2, cyclooxygenase 2; ES, embryonic stem; GDF-9 or Gdf9, growth differentiation factor-9; Has2, hyaluronan synthase 2; HC, heavy chain; hCG, human CG; hprt, hypoxanthine-guanine phosphoribosyl transferase; ITI, inter--trypsin inhibitor; LPS, lipopolysaccharide; PGK, phosphoglycerate kinase; Ptx3 or PTX3, pentraxin 3; Tnfip6, TNF-induced protein 6.
Received for publication December 17, 2001. Accepted for publication March 14, 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-inhibitor binding to hyaluronan in the cumulus extracellular matrix is required for optimal ovulation and development of mouse oocytes. Biol Reprod 61:436–44324J Q T cells from identical twins discordant for type I diabetes. Proc Natl Acad Sci USA 97:7411–7416-Inhibin is a tumor-suppressor gene with gonadal specificity in mice. Nature 360:313–319[CrossRef][Medline]
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A. Inforzato, V. Rivieccio, A. P. Morreale, A. Bastone, A. Salustri, L. Scarchilli, A. Verdoliva, S. Vincenti, G. Gallo, C. Chiapparino, et al. Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization J. Biol. Chem., April 11, 2008; 283(15): 10147 - 10161. [Abstract] [Full Text] [PDF]
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R. M. Popovici, M. S. Krause, J. Jauckus, A. Germeyer, I. S. Brum, C. Garlanda, T. Strowitzki, and M. von Wolff The Long Pentraxin PTX3 in Human Endometrium: Regulation by Steroids and Trophoblast Products Endocrinology, March 1, 2008; 149(3): 1136 - 1143. [Abstract] [Full Text] [PDF]
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Y. Yamashita, I. Kawashima, Y. Yanai, M. Nishibori, J. S. Richards, and M. Shimada Hormone-Induced Expression of Tumor Necrosis Factor {alpha}-Converting Enzyme/A Disintegrin and Metalloprotease-17 Impacts Porcine Cumulus Cell Oocyte Complex Expansion and Meiotic Maturation via Ligand Activation of the Epidermal Growth Factor Receptor Endocrinology, December 1, 2007; 148(12): 6164 - 6175. [Abstract] [Full Text] [PDF]
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F. Cillo, T. A L Brevini, S. Antonini, A. Paffoni, G. Ragni, and F. Gandolfi Association between human oocyte developmental competence and expression levels of some cumulus genes Reproduction, November 1, 2007; 134(5): 645 - 650. [Abstract] [Full Text] [PDF]
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A. Cotena, V. Maina, M. Sironi, B. Bottazzi, P. Jeannin, A. Vecchi, N. Corvaia, M. R. Daha, A. Mantovani, and C. Garlanda Complement Dependent Amplification of the Innate Response to a Cognate Microbial Ligand by the Long Pentraxin PTX3 J. Immunol., November 1, 2007; 179(9): 6311 - 6317. [Abstract] [Full Text] [PDF]
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 K. R. Dunning, M. Lane, H. M. Brown, C. Yeo, R. L. Robker, and D. L. Russell Altered composition of the cumulus-oocyte complex matrix during in vitro maturation of oocytes Hum. Reprod., November 1, 2007; 22(11): 2842 - 2850. [Abstract] [Full Text] [PDF]
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L. Scarchilli, A. Camaioni, B. Bottazzi, V. Negri, A. Doni, L. Deban, A. Bastone, G. Salvatori, A. Mantovani, G. Siracusa, et al. PTX3 Interacts with Inter-{alpha}-trypsin Inhibitor: IMPLICATIONS FOR HYALURONAN ORGANIZATION AND CUMULUS OOPHORUS EXPANSION J. Biol. Chem., October 12, 2007; 282(41): 30161 - 30170. [Abstract] [Full Text] [PDF]
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S. Tranguch, A. Chakrabarty, Y. Guo, H. Wang, and S. K Dey Maternal Pentraxin 3 Deficiency Compromises Implantation in Mice Biol Reprod, September 1, 2007; 77(3): 425 - 432. [Abstract] [Full Text] [PDF]
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 D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]
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 X. He, B. Han, and M. Liu Long pentraxin 3 in pulmonary infection and acute lung injury Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1039 - L1049. [Abstract] [Full Text] [PDF]
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 S. Jaillon, G. Peri, Y. Delneste, I. Fremaux, A. Doni, F. Moalli, C. Garlanda, L. Romani, H. Gascan, S. Bellocchio, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps J. Exp. Med., April 16, 2007; 204(4): 793 - 804. [Abstract] [Full Text] [PDF]
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 F. J. Diaz, K. Wigglesworth, and J. J. Eppig Oocytes determine cumulus cell lineage in mouse ovarian follicles J. Cell Sci., April 15, 2007; 120(8): 1330 - 1340. [Abstract] [Full Text] [PDF]
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M. Hsieh, D. Lee, S. Panigone, K. Horner, R. Chen, A. Theologis, D. C. Lee, D. W. Threadgill, and M. Conti Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation Mol. Cell. Biol., March 1, 2007; 27(5): 1914 - 1924. [Abstract] [Full Text] [PDF]
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T. Takahashi, J. D. Morrow, H. Wang, and S. K. Dey Cyclooxygenase-2-derived Prostaglandin E2 Directs Oocyte Maturation by Differentially Influencing Multiple Signaling Pathways J. Biol. Chem., December 1, 2006; 281(48): 37117 - 37129. [Abstract] [Full Text] [PDF]
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K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]
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O. Yoshino, H. E. McMahon, S. Sharma, and S. Shimasaki A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse PNAS, July 11, 2006; 103(28): 10678 - 10683. [Abstract] [Full Text] [PDF]
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C. Agca, J. E Ries, S. J Kolath, J.-H. Kim, L. J Forrester, E. Antoniou, K. M Whitworth, N. Mathialagan, G. K Springer, R. S Prather, et al. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression Reproduction, July 1, 2006; 132(1): 133 - 145. [Abstract] [Full Text] [PDF]
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S. Mazerbourg and A. J.W. Hsueh Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands Hum. Reprod. Update, July 1, 2006; 12(4): 373 - 383. [Abstract] [Full Text] [PDF]
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I. Hernandez-Gonzalez, I. Gonzalez-Robayna, M. Shimada, C. M. Wayne, S. A. Ochsner, L. White, and J. S. Richards Gene Expression Profiles of Cumulus Cell Oocyte Complexes during Ovulation Reveal Cumulus Cells Express Neuronal and Immune-Related Genes: Does this Expand Their Role in the Ovulation Process? Mol. Endocrinol., June 1, 2006; 20(6): 1300 - 1321. [Abstract] [Full Text] [PDF]
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S. A. Pangas, X. Li, E. J. Robertson, and M. M. Matzuk Premature Luteinization and Cumulus Cell Defects in Ovarian-Specific Smad4 Knockout Mice Mol. Endocrinol., June 1, 2006; 20(6): 1406 - 1422. [Abstract] [Full Text] [PDF]
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C. Yan, J. A. Elvin, Y.-N. Lin, L. A. Hadsell, J. Wang, F. J. DeMayo, and M. M. Matzuk Regulation of Growth Differentiation Factor 9 Expression in Oocytes In Vivo: A Key Role of the E-Box Biol Reprod, June 1, 2006; 74(6): 999 - 1006. [Abstract] [Full Text] [PDF]
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B. Bottazzi, A. Bastone, A. Doni, C. Garlanda, S. Valentino, L. Deban, V. Maina, A. Cotena, F. Moalli, L. Vago, et al. The long pentraxin PTX3 as a link among innate immunity, inflammation, and female fertility J. Leukoc. Biol., May 1, 2006; 79(5): 909 - 912. [Abstract] [Full Text] [PDF]
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 A. Paffoni, G. Ragni, A. Doni, E. Somigliana, F. Pasqualini, L. Restelli, G. Pardi, A. Mantovani, and C. Garlanda Follicular Fuid Levels of the Long Pentraxin PTX3 Reproductive Sciences, April 1, 2006; 13(3): 226 - 231. [Abstract] [PDF]
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A. Doni, M. Michela, B. Bottazzi, G. Peri, S. Valentino, N. Polentarutti, C. Garlanda, and A. Mantovani Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-{gamma} J. Leukoc. Biol., April 1, 2006; 79(4): 797 - 802. [Abstract] [Full Text] [PDF]
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 P. Baruah, A. Propato, I. E. Dumitriu, P. Rovere-Querini, V. Russo, R. Fontana, D. Accapezzato, G. Peri, A. Mantovani, V. Barnaba, et al. The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens Blood, January 1, 2006; 107(1): 151 - 158. [Abstract] [Full Text] [PDF]
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S. A. Pangas and M. M. Matzuk The Art and Artifact of GDF9 Activity: Cumulus Expansion and the Cumulus Expansion-Enabling Factor Biol Reprod, October 1, 2005; 73(4): 582 - 585. [Abstract] [Full Text] [PDF]
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S. A. Kuznetsova, A. J. Day, D. J. Mahoney, M. S. Rugg, D. F. Mosher, and D. D. Roberts The N-terminal Module of Thrombospondin-1 Interacts with the Link Domain of TSG-6 and Enhances Its Covalent Association with the Heavy Chains of Inter-{alpha}-trypsin Inhibitor J. Biol. Chem., September 2, 2005; 280(35): 30899 - 30908. [Abstract] [Full Text] [PDF]
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J. M. A. Tullet, V. Pocock, J. H. Steel, R. White, S. Milligan, and M. G. Parker Multiple Signaling Defects in the Absence of RIP140 Impair Both Cumulus Expansion and Follicle Rupture Endocrinology, September 1, 2005; 146(9): 4127 - 4137. [Abstract] [Full Text] [PDF]
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M. S. Rugg, A. C. Willis, D. Mukhopadhyay, V. C. Hascall, E. Fries, C. Fulop, C. M. Milner, and A. J. Day Characterization of Complexes Formed between TSG-6 and Inter-{alpha}-inhibitor That Act as Intermediates in the Covalent Transfer of Heavy Chains onto Hyaluronan J. Biol. Chem., July 8, 2005; 280(27): 25674 - 25686. [Abstract] [Full Text] [PDF]
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W. Yan, L. Ma, P. Stein, S. A. Pangas, K. H. Burns, Y. Bai, R. M. Schultz, and M. M. Matzuk Mice Deficient in Oocyte-Specific Oligoadenylate Synthetase-Like Protein OAS1D Display Reduced Fertility Mol. Cell. Biol., June 1, 2005; 25(11): 4615 - 4624. [Abstract] [Full Text] [PDF]
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J. S. Richards, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, E. Teuling, Y. Lo, D. Boerboom, A. E. Falender, K. H. Doyle, R. G. LeBaron, V. Thompson, et al. Regulated Expression of ADAMTS Family Members in Follicles and Cumulus Oocyte Complexes: Evidence for Specific and Redundant Patterns During Ovulation Biol Reprod, May 1, 2005; 72(5): 1241 - 1255. [Abstract] [Full Text] [PDF]
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J. Yang, S. Medvedev, J. Yu, L. C. Tang, J. E. Agno, M. M. Matzuk, R. M. Schultz, and N. B. Hecht Absence of the DNA-/RNA-binding protein MSY2 results in male and female infertility PNAS, April 19, 2005; 102(16): 5755 - 5760. [Abstract] [Full Text] [PDF]
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H.-G. Wisniewski, E. S. Snitkin, C. Mindrescu, M. H. Sweet, and J. Vilcek TSG-6 Protein Binding to Glycosaminoglycans: FORMATION OF STABLE COMPLEXES WITH HYALURONAN AND BINDING TO CHONDROITIN SULFATES J. Biol. Chem., April 15, 2005; 280(15): 14476 - 14484. [Abstract] [Full Text] [PDF]
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J. E. I. Gittens, K. J. Barr, B. C. Vanderhyden, and G. M. Kidder Interplay between paracrine signaling and gap junctional communication in ovarian follicles J. Cell Sci., January 1, 2005; 118(1): 113 - 122. [Abstract] [Full Text] [PDF]
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E. Nagyova, A. Camaioni, R. Prochazka, and A. Salustri Covalent Transfer of Heavy Chains of Inter-{alpha}-Trypsin Inhibitor Family Proteins to Hyaluronan in In Vivo and In Vitro Expanded Porcine Oocyte-Cumulus Complexes Biol Reprod, December 1, 2004; 71(6): 1838 - 1843. [Abstract] [Full Text] [PDF]
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S. A. Pangas, C. J. Jorgez, and M. M. Matzuk Growth Differentiation Factor 9 Regulates Expression of the Bone Morphogenetic Protein Antagonist Gremlin J. Biol. Chem., July 30, 2004; 279(31): 32281 - 32286. [Abstract] [Full Text] [PDF]
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M. Rusnati, M. Camozzi, E. Moroni, B. Bottazzi, G. Peri, S. Indraccolo, A. Amadori, A. Mantovani, and M. Presta Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis Blood, July 1, 2004; 104(1): 92 - 99. [Abstract] [Full Text] [PDF]
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S. N. Diniz, R. Nomizo, P. S. Cisalpino, M. M. Teixeira, G. D. Brown, A. Mantovani, S. Gordon, L. F. L. Reis, and A. A. M. Dias PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages J. Leukoc. Biol., April 1, 2004; 75(4): 649 - 656. [Abstract] [Full Text] [PDF]
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A. Salustri, C. Garlanda, E. Hirsch, M. De Acetis, A. Maccagno, B. Bottazzi, A. Doni, A. Bastone, G. Mantovani, P. B. Peccoz, et al. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization Development, April 1, 2004; 131(7): 1577 - 1586. [Abstract] [Full Text] [PDF]
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D. Mukhopadhyay, A. Asari, M. S. Rugg, A. J. Day, and C. Fulop Specificity of the Tumor Necrosis Factor-induced Protein 6-mediated Heavy Chain Transfer from Inter-{alpha}-trypsin Inhibitor to Hyaluronan: IMPLICATIONS FOR THE ASSEMBLY OF THE CUMULUS EXTRACELLULAR MATRIX J. Biol. Chem., March 19, 2004; 279(12): 11119 - 11128. [Abstract] [Full Text] [PDF]
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 S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson The Bone Morphogenetic Protein System In Mammalian Reproduction Endocr. Rev., February 1, 2004; 25(1): 72 - 101. [Abstract] [Full Text] [PDF]
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K. H. Burns, G. E. Owens, S. C. Ogbonna, J. H. Nilson, and M. M. Matzuk Expression Profiling Analyses of Gonadotropin Responses and Tumor Development in the Absence of Inhibins Endocrinology, October 1, 2003; 144(10): 4492 - 4507. [Abstract] [Full Text] [PDF]
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S. Cukurcam, C. Hegele-Hartung, and U. Eichenlaub-Ritter Meiosis-activating sterol protects oocytes from precocious chromosome segregation Hum. Reprod., September 1, 2003; 18(9): 1908 - 1917. [Abstract] [Full Text] [PDF]
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C. M. Milner and A. J. Day TSG-6: a multifunctional protein associated with inflammation J. Cell Sci., May 15, 2003; 116(10): 1863 - 1873. [Abstract] [Full Text] [PDF]
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C. Fulop, S. Szanto, D. Mukhopadhyay, T. Bardos, R. V. Kamath, M. S. Rugg, A. J. Day, A. Salustri, V. C. Hascall, T. T. Glant, et al. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice Development, May 15, 2003; 130(10): 2253 - 2261. [Abstract] [Full Text] [PDF]
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 A. Abderrahim-Ferkoune, O. Bezy, C. Chiellini, M. Maffei, P. Grimaldi, F. Bonino, N. Moustaid-Moussa, F. Pasqualini, A. Mantovani, G. Ailhaud, et al. Characterization of the long pentraxin PTX3 as a TNF{alpha}-induced secreted protein of adipose cells J. Lipid Res., May 1, 2003; 44(5): 994 - 1000. [Abstract] [Full Text] [PDF]
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B. Bussolati, G. Peri, G. Salvidio, D. Verzola, A. Mantovani, and G. Camussi The Long Pentraxin Ptx3 Is Synthesized in IgA Glomerulonephritis and Activates Mesangial Cells J. Immunol., February 1, 2003; 170(3): 1466 - 1472. [Abstract] [Full Text] [PDF]
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H. Chang, C. W. Brown, and M. M. Matzuk Genetic Analysis of the Mammalian Transforming Growth Factor-{beta} Superfamily Endocr. Rev., December 1, 2002; 23(6): 787 - 823. [Abstract] [Full Text] [PDF]
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