BOR - Papers in Press, published online ahead of print
May 25, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.042127
BIOLOGY OF REPRODUCTION 73, 582–585 (2005)
DOI: 10.1095/biolreprod.105.042127
© 2005 by the Society for the Study of Reproduction, Inc.
The Art and Artifact of GDF9 Activity: Cumulus Expansion and the Cumulus Expansion-Enabling Factor1
Stephanie A. Pangas 2 , and
Martin M. Matzuk
Departments of Pathology, Molecular and Cellular Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT
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The process of cumulus cell expansion is critical for normal fertility. Oocyte-produced growth and differentiation factor 9 (GDF9) has been thought to play a leading role in this process. Recent studies both support and refute this hypothesis. Central to understanding the physiology of GDF9 is the use of recombinant ligand in in vitro assays. There are several laboratories that currently produce recombinant GDF9 preparations that appear to show variable effects on granulosa cell gene expression and cumulus cell expansion. Several of these studies are reviewed here. Standardization in preparation for recombinant GDF9, as well as a more biochemical analysis of the oocyte-secreted forms of GDF9, may help to resolve the conflicts currently seen in the literature.
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INTRODUCTION
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From the time of primordial follicle formation within the ovary, the growth, development, and reproductive competence of the oocyte is directly tied to its association with somatic granulosa cells [1–3]. Perturbations in oocyte-somatic cell communication, both preovulation and postovulation, can result in the loss of fertility. Following the preovulatory LH surge, intercellular connections between the oocyte and cumulus cells are broken, but cumulus cells undergo a process of cumulus expansion that continues to bind the cumulus cells to the oocyte throughout the ovulatory process and in subsequent fertilization. Characteristics of the expansion include the secretion of a hyaluronic acid rich matrix by the cumulus cells and expression of a number of other proteins required for matrix formation and retention [4–7]. A number of reviews are available to the reader that fully describe the physiology and significance of cumulus cell expansion [8–12].
Originally, it had been discovered that mouse oocyte-cumulus cell complexes that had the oocyte removed (oocytectomized [OOX]) had two requirements for expansion: first, the OOX complexes had to be stimulated with FSH, and second, OOX complexes needed to be cocultured with fully-grown denuded oocytes and not those from early antral follicles [13, 14]. This in vitro assay suggested that fully-grown oocytes produce a secreted factor (called the cumulus expansion-enabling factor [CEEF]) that allows cumulus cells to respond to FSH [9, 13, 14]. Various proteins have been evaluated as to whether they might be the CEEF [15–17]. Both transforming growth factor ß (TGFß), and, more recently, growth and differentiation factor 9 (GDF9) have been shown to promote cumulus expansion in vitro [15, 18–20]. GDF9 was a particularly attractive candidate CEEF because it was the first oocyte-specific gene shown to cause expansion [18], and oocyte-conditioned media were known to promote cumulus cell expansion in vitro [13, 14]. In addition, treatment of granulosa cells in vitro with recombinant mouse GDF9 (rmGDF9) directly induces, within 5 h, transcription of a suite of genes characteristic of cumulus cell expansion in vivo, including hyaluronan synthase 2 (Has2), prostaglandin-endoperoxide synthase 2 (Ptgs2), pentraxin 3 (Ptx3), and tumor necrosis factor alpha induced protein 6 (Tnfaip6), while repressing others (luteinizing hormone/choriogonadotropin receptor [Lhcgr] and plasminogen activator, urokinase [Plau]) [6, 18] (Fig. 1). GDF9 can promote these changes in gene expression and cumulus expansion even in the absence of FSH [6, 18, 21, 22]. However, the role of GDF9 as the CEEF remains controversial, in part because of the publication of several contradictory new studies.
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FIG. 1. Possible downstream targets of GDF9 and BMP15. GDF9 and BMP15 are secreted from the oocyte and act on target cells that may include both cumulus and mural granulosa cells. Genes colored in green have been shown to be upregulated by recombinant GDF9 in vitro; genes shown in red, downregulated. Not all genes listed have been verified as direct targets of GDF9. FSH receptor (Fshr) has been shown to be downregulated by BMP15 only [51]. An asterisk indicates a gene with variable regulation by different preparations of recombinant GDF9. Cyp17a1, cytochrome P450, family 17, subfamily a, polypeptide 1; Kitl, kit ligand; Star, steroidogenic acute regulatory protein. Superscript numbers indicate references
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IS GDF9 SUFFICIENT FOR CUMULUS CELL EXPANSION?
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A recent paper has suggested that oocyte-produced GDF9 is insufficient for promoting cumulus cell expansion and that another oocyte-specific factor may be the CEEF [23]. This study was conducted using two new reagents: neutralizing antibodies to GDF9 and partially purified mouse GDF9. A neutralizing antibody to human GDF9 that maps to an epitope in the C-terminal region of GDF9 was generated and used to show that addition of this antibody to cocultures of denuded mouse oocytes and granulosa cells could only partially inhibit mitogenic properties of oocytes [24]. Given the repertoire of secreted factors produced by the oocyte [10], the identification of other secreted factors that control granulosa cell proliferation may not come as a surprise. Still, about half of oocyte mitogenic activity is accounted for by GDF9 [24], and this indicates that GDF9 is a prominent player in oocyte-granulosa cell function.
Because previous studies pointed to GDF9 as the CEEF, it was surprising that, in a subsequent study, the GDF9 immunoneutralizing antibody had no effect on expansion during cocultures with denuded oocytes, while fully inhibiting recombinant GDF9-induced cumulus expansion [23]. This suggests that the oocyte produces something in addition to GDF9 that is required for cumulus cell expansion [23]. Furthermore, combined immunoneutralization with antibodies against TGFß and GDF9 failed to antagonize oocyte-induced cumulus expansion; thus, it was hypothesized that GDF9, like TGFß, cannot be the key factor regulating cumulus expansion in mice [23] and that there must be an additional oocyte-produced CEEF.
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IS GDF9 NECESSARY FOR CUMULUS CELL EXPANSION?
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In contrast to the immunoneutralization data, some of the most convincing data for GDF9 as the sole CEEF in oocytes comes from another recently published study. By using a long double-stranded RNA interference (RNAi) approach, Gui and Joyce [25] show that Gdf9 mRNA can be efficiently knocked down in oocytes, resulting in oocytes that do not produce detectable GDF9 protein. These Gdf9 knockdown oocytes, in turn, are unable to stimulate FSH-induced cumulus cell expansion, unlike control oocytes, or oocytes with an RNAi knockdown of the Gdf9 related gene, bone morphogenetic protein 15 (Bmp15). These GDF9-deficient oocytes failed to stimulate Has2 and Ptgs2 mRNA in cumulus cells to the level of control oocytes. These data argue that GDF9 is the only oocyte factor necessary for cumulus cell expansion. Thus, the GDF9 knockdown oocytes behave similarly to Gdf9 null oocytes (from Gdf9 knockout mice) in their inability to promote cumulus cell expansion in OOX complexes [20]. And although it has been argued that Gdf9 null oocytes may be developmentally compromised and that this may explain their inability to expand cumulus cells in vitro [20, 23], the same argument cannot be applied to the Gdf9 RNAi-treated oocytes. In addition, these new RNAi experiments circumvent the issues of production and processing differences that may occur during the generation of recombinant GDF9 by directly removing GDF9 from its source—the oocyte.
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VARIATIONS IN RECOMBINANT GDF9 ACTIVITY
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Thus, two different experimental approaches to GDF9 activity—one, a loss of function through RNAi; the other, the use of recombinant GDF9 and neutralizing antibodies in a culture system—have given contradictory answers to questions regarding GDF9 as the sole oocyte CEEF, even though the in vitro assays appear to be the same. The most likely source of this problem may be recombinant protein activity. The Gilchrist laboratory preparations of mouse GDF9 require both FSH and GDF9 to induce cumulus expansion and Has2 expression [23], but preparations of mouse GDF9 from our laboratory have been shown to induce cumulus expansion and Has2 and gremlin (Grem1) expression alone or in combination with FSH [18, 21, 22]. So far, it is not clear what the differences are between the different mouse GDF9 preparations. Subsequent to our initial production of rmGDF9, our recombinant media have been made from stable-transfected Chinese hamster ovary cell lines that secrete mouse GDF9 under serum-free conditions without the addition of heparin. Mouse GDF9 from the Gilchrist and Ritvos laboratories [23, 26] are from conditioned media of stable-transfected human embryonic kidney 293H cells in media containing heparin, and in some instances are partially purified by hydrophobic interaction chromatography [23]. It is not known whether purification alters the activity of recombinant GDF9. Unlike most other TGFß superfamily proteins, GDF9 and its close oocyte-specific relative BMP15 [27, 28], as well as GDF3 and Lefty, do not contain the cysteine residue that creates the interchain disulfide bond necessary for covalent linkage of the subunits [29, 30]. Unpurified recombinant GDF9 and BMP15, however, have been shown to form noncovalent dimers in solution when expressed from human 293T cells [31]. It is possible that partial purification somehow alters the conformation of the GDF9 protein, or that purification changes the monomer-to-dimer ratio in favor of the monomer, and these changes may affect its signaling properties.
Heparin is used in some recombinant GDF9 preparations, and it is unclear how the addition of heparin affects GDF9 signaling. In our experience, a similar subset of genes appears to be induced with rmGDF9 media with and without heparin [6, 18, 21], with some exceptions (see below). Besides cumulus cell expansion, other key differences can be seen from gene expression changes when granulosa cells are treated with the two preparations of GDF9. For instance, although we have gene expression data for several independent microarray experiments for granulosa cells treated with GDF9, we never observe a significant increase in the inhibin 
subunit [6] and see variable differences in expression for the inhibin ßB subunit. Granulosa cells treated with our recombinant GDF9 medium that contains heparin has shown small, but inconsistent, changes in the regulation of the inhibin ßB subunit [6], while recombinant GDF9 made without heparin has no effect on inhibin ßB subunit levels [21]. However, other groups using preparations of GDF9 that include heparin have seen increases in both inhibin and inhibin ßB, albeit in nonmouse tissues [26, 32, 33]. Even though in vitro data give conflicting information regarding induction of inhibin and inhibin ßB, there is little to support an in vivo role for the regulation of these two genes by GDF9. Mice null for Gdf9 continue to express inhibin ßB and also inappropriately overexpress the inhibin subunit [34]. Mice null for both Gdf9 and Inha have follicles that develop further (multilayer preantral follicles) than mice null for only Gdf9 (one-layer primary follicles), suggesting that a more likely role for GDF9 is to directly or indirectly suppress inhibin [34, 35]. Clearly, in these two mouse models, GDF9 is not required for inhibin and ßB mRNA induction.
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FUTURE STUDIES FOR GDF9 IN CUMULUS EXPANSION
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The requirement for FSH in oocyte- or GDF9-induced cumulus expansion also needs further investigation. Both of the contradictory new studies mentioned in this review [23, 25] require FSH for cumulus expansion, as in the original description of the CEEF [13]. In addition, it has been shown that MAPK activity in cumulus cells is required for FSH and GDF9-induced expansion [22, 36]. In the case of GDF9-only induced expansion, it is not clear whether this is a direct signaling response of the cells to GDF9 or whether another protein may be present in the recombinant protein preparation. Although the signaling pathway for GDF9 is only beginning to be understood [26, 32, 37, 38], it is known that members of the TGFß superfamily can activate the MAPK pathway [39]. Clearly, other in vitro assays beyond cumulus expansion have established that GDF9 does not require FSH (or serum) to directly induce changes in gene expression that are consistent with the changes observed during cumulus expansion such as the regulation of Has2, Ptgs2, Plau, and Ptx3 [6, 18, 21].
Some of these issues may be resolved with establishment of a standardization between preparations. Ideally, the quality and quantity of activity for recombinant proteins should be based on known biological functions. For example, the TGFß-related proteins, inhibin and activin, were discovered based on their abilities to regulate pituitary FSH [40–42], and in vitro anterior pituitary bioassays can be used to verify purified protein activity [40, 43]. It could be argued that cumulus expansion in the absence of FSH would be the sine qua non of bioassays for GDF9. Perhaps it still may be—but the field will have to decide.
Even though there are unresolved issues regarding the requirement for FSH in GDF9-induced cumulus expansion, the studies from Dragovic et al. [23] and Gui and Joyce [25] both use similar assays (with FSH) during in vitro assays of cumulus expansion of OOX complexes, but arrive at vastly different conclusions. The key to understanding the role of GDF9 in cumulus expansion will require a better understanding of the regulation of GDF9 production, its intracellular processing and secretion by the oocyte, its extracellular processing, and how GDF9 signals to cumulus cells. Many questions still remain. Are there processing differences in the various GDF9-producing cell lines (e.g., what is the ratio of inactive incompletely processed mature GDF9)? Do processing/secretion differences in GDF9 explain why only fully-grown oocytes and not early antral oocytes stimulate cumulus expansion in in vitro assays? What are the effects of alterations in the processing of the N-linked oligosaccharides since mature GDF9 is glycosylated? Does GDF9 form heterodimers with BMP15 in vivo similarly to what has been demonstrated in vitro [31], and what, if any, are the differences in bioactivity between heterodimers and homodimers of each ligand? Does the new GDF9 neutralizing monoclonal antibody recognize all of the oocyte-secreted forms of GDF9 in solution (including possible heterodimers with BMP15) and can the antibody bioneutralize them? An important test will be to use the neutralizing GDF9 antibody against the different laboratory preparations of rmGDF9 to justify whether the different preparations of GDF9 indeed have different bioactivities or whether the neutralizing antibody cannot recognize some forms of GDF9. Furthermore, because there are no oocyte-like cell lines from which to produce GDF9, a more biochemical analysis of GDF9 processing and secretion is warranted, so that these conditions may be mimicked in cell culture production, or so that antibodies can be made to forms secreted by the oocyte.
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CONCLUSIONS
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With the production of any recombinantly produced ligand comes the question of whether or not it mimics the naturally produced protein. Clearly, different preparations of GDF9 have different activities in terms of cumulus cell expansion and regulation of gene expression. Thus, it has become apparent that the field of reproduction requires a consistent, accurate, and reliable source of recombinant GDF9. Studies have demonstrated that GDF9-regulated genes, such as Has2, Ptgs2, and Grem1 can be excellent predictors of fertilization and embryo quality in humans [44]. The use of recombinant ligands is critical for these gene discovery processes. Data regarding mutations in sheep GDF9 and BMP15 and its receptors suggest that there are species-specific differences that also need clarification [45]. Recently, a mutation in human BMP15 has been identified that causes ovarian dysfunction [46]. Additional data gained from studying human GDF9 and BMP15 are likely to reveal important oocyte functions that, when altered, will lead to infertility and disease in women. It will be difficult for progress to be made until the issues and standardization of GDF9 production and activity are resolved.
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FOOTNOTES
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1 Supported by National Institutes of Health grant HD33438 and the Specialized Cooperative Centers Program in Reproductive Research (HD07495) to M.M.M. and the National Institutes of Health National Research Service Award (F32 HD46335-01A1) to S.A.P. 
2 Correspondence: Stephanie A. Pangas, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. FAX: 713 798 5833; spangas{at}bcm.tmc.edu
Received: 19 March 2005.
First decision: 11 April 2005.
Accepted: 24 May 2005.
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P. Laissue, S. Christin-Maitre, P. Touraine, F. Kuttenn, O. Ritvos, K. Aittomaki, N. Bourcigaux, L. Jacquesson, P. Bouchard, R. Frydman, et al.
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TOP
ABSTRACT
INTRODUCTION
