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RESEARCH |
AgResearch, Wallaceville Animal Research Centre, Ward Street, PO Box 40063, Upper Hutt, New Zealand, 1 Program for Developmental and Reproductive Biology, Biomedicum Helsinki, and Department of Bacteriology and Immunology, Haartman Institute, 00014 University of Helsinki, Helsinki, Finland and 2 School of Biological and Medical Sciences, Oxford Brookes University, Headington, Oxford, United Kingdom
Correspondence should be addressed to K P McNatty; Email: ken.mcnatty{at}agresearch.co.nz
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Introduction |
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Materials and Methods |
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Granulosa cell collection
Ovaries were collected from ewes and cows following slaughter at the local abattoir, transported back to the laboratory at ambient temperature, washed in a 3% bleach solution in PBS for 5 min, rinsed twice in PBS and stored in Leibovitz L-15 media. Follicles, approximately 1–2 mm (ewes) or 1–4.5 mm (cows) in diameter, were dissected from the ovaries and stored in Leibovitz L-15 media until collection of the granulosa cells. Subsequently, the follicles were cut in half and the granulosa cells were removed using a wire loop. For both species, the oocyte-cumulus cell complexes, isolated oocytes and follicular debris were visualized using a dissecting microscope and most, if not all, were removed from the cells using a glass pipette. The granulosa cells were then recovered following centrifugation at 300 g for 5 min at room temperature after one wash in 5 ml Leibovitz L-15 media.
Culture of granulosa cells for determination of 3H-thymidine incorporation
The cells were washed a further time in 5 ml M199 (Earle’s, Sigma) with 100 U/ml penicillin, 100 µg/ml streptomycin, 2 mM GlutaMAX-1 (Invitrogen), 0.3 mg/ml polyvinyl alcohol (Sigma) and 0.23 mM sodium pyruvate (Sigma) and resuspended using a syringe and needle in M199. Cell viability was determined using trypan blue exclusion. Granulosa cells (20 000 viable cells in a total volume of 125 µl per well) were cultured in M199 with varying amounts of conditioned media from control (untransfected), GDF9 expressing or BMP15 expressing 293H cells at 37 °C in a 5% CO2 incubator. After 18 h of culture, methyl-3H-thymidine (Perkin Elmer, Boston, MA, USA; 20 Ci/mmol, 0.4 µCi per well) was added to each well and the culture continued for an additional 6 h after which the cells were harvested with a cell harvester onto a thin filter mat. Incorporation of 3H-thymidine was determined using a Wallac Trilux MicroBeta 1450 liquid scintillation counter (Biolab, Auckland, NZ). Treatments included 1000 or 2000 ng/ml of mGDF9 or oGDF9, 4 or 8 ng/ml of oBMP15, or a combination of 1000 ng/ml mGDF9 with 4 ng/ml oBMP15, or 1000 ng/ml oGDF9 with 4 ng/ml oBMP15. These concentrations of GDF9 and BMP15 were the maximum that could be tested within the volume limits of the bioassay based on the use of a maximum of 40% of conditioned media. In addition, the effects of diluting the oGDF9 (200, 100, 20 and 10 ng/ml) while oBMP15 concentrations were held constant at 4 ng/ml, and diluting the oBMP15 (2, 0.8, 0.08 and 0.04 ng/ml) while oGDF9 concentrations were held constant at 1000 ng/ml were determined. All control wells were treated with an identical volume of conditioned media from untransfected 293H cells. For all assays, all treatments were applied at least in triplicate with a minimum of three independent pools (range 3–11) of granulosa cells being tested. Within an assay, individual values outside 30% of the mean value for the treatment were discarded. Points in which at least two of the replicates were not within 30% of each other were regarded as missing data.
Culture of granulosa cells for determination of progesterone and inhibin production
The cells were washed a further time in 5 ml McCoys 5a media (Sigma) with 100 U/ml penicillin, 100 µg/ml streptomycin, 2 mM GlutaMAX-1 and 0.1% BSA and resuspended using a syringe and needle in McCoys 5a media. Cell viability was determined using trypan blue exclusion. Granulosa cells (100 000 viable ovine and 75 000 viable bovine cells per well; 250 µl total volume) were cultured in McCoys 5a media containing 5 ng/ml sodium selenite (Sigma), 10 ng/ml bovine insulin (Sigma), 5 µg/ml holotransferrin (Invitrogen), 30 ng/ml androstenedione (Sigma), 3 ng/ml ovine follicle-stimulating hormone (oFSH; prepared in our laboratory, 1.4 x USDA-oFSH-19-SIAFP RP2), 1 ng/ml IGF-1 (Long-R3, Gro-Pep, Sydney, Australia) with varying amounts of conditioned media from control (untransfected) GDF9 expressing and/or BMP15 expressing 293H cells. Cells were cultured at 37 °C in a humidified incubator with a 5% C02 in air gas phase. Every 48 h, 200 µl of media was removed from each well and replaced with 200 µl of warmed media that had been prepared at the start of the culture and stored at 4 °C. Media samples from the last 48 h of treatment were collected on day 6 of treatment and frozen at –20 °C for later determination of progesterone and inhibin concentrations by RIA. Treatments included the addition of 1000 or 2000 ng/ml of mGDF9 or oGDF9, 4 or 8 ng/ml oBMP15 or the combination of 1000 ng/ml mGDF9 with 4 ng/ml oBMP15, or 1000 ng/ml oGDF9 with 4 ng/ml oBMP15. In addition, the effects of diluting oGDF9 (200, 100, 20 and 10 ng/ml) while oBMP15 concentrations were held constant at 4 ng/ml or diluting oBMP15 (2, 0.8, 0.08 and 0.04 ng/ml) while oGDF9 concentrations were held constant at 1000 ng/ml were determined in some instances. All treatments were applied at least in triplicate to a minimum of five independent pools (range 5–15) of granulosa cells for each species. Within an assay, individual values outside of 20% of the mean value for the treatment were discarded. Points in which at least two of the replicates were not within 20% of each other were regarded as missing data.
Determination of progesterone and inhibin concentrations in media
The concentrations of progesterone in media were determined by RIA as described previously (Asher 1990). The sensitivity of the assay (90% maximum binding) was 17 pg/ml and the intra- and inter-assay coefficients of variations, averaged for a standard pool sample at approximately 20%, 50% and 80% binding, were overall 7.8% and 7.5% respectively. No samples were below the sensitivity of the assay. The concentrations of inhibin were determined by RIA as previously described (McNatty et al. 1992). The antibody to inhibin detects 31 kDa inhibin and the pro-
C subunit (Robertson et al. 1989). The intra- and inter-assay coefficients of variations were 11.0% and 11.7% respectively. The sensitivity of the assay was 13 IU/ml bINH R-90/1 standard: no samples were below the sensitivity of the assay.
Statistical analysis
The differences between treatments and control were determined using the two-tailed paired t-test function in Microsoft Excel 2003. The control samples always contained an equivalent amount of untransfected 293H conditioned media as the treated samples. The values for 3H-thymidine incorporation and inhibin were transformed (natural log) prior to analyses. Differences in responses between treatments were determined using the two-tailed t-test function in Microsoft Excel 2003 using the ratio to control values. For ease of presentation, all values have been converted to a ratio of the appropriate controls which were assigned a value of 1.00. The geometric means (and 95% confidence limits) for 3H-thymidine incorporation into ovine and bovine granulosa cells treated with 293H control media were 122 (88, 169) and 848 (563, 1278) c.p.m./well respectively. The means ± S.E.M. for progesterone production by ovine and bovine granulosa cells treated with 293H control media were 24 ± 2 and 66 ± 6 ng/well respectively. The geometric means (and 95% confidence limits) for inhibin production by ovine and bovine granulosa cells treated with 293H control media were 178 (126, 250) and 83 (60, 115) IU/well respectively.
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). oBMP15 stimulated thymidine incorporation at the highest dose.The addition of either mGDF9 or oGDF9 with oBMP15 resulted in a significant stimulation of thymidine incorporation. This effect was in contrast to the suppression observed when mGDF9 was added alone, or the absence of a significant increase or decrease with either oGDF9 or oBMP15 alone at equivalent doses. When oGDF9 was serially diluted from 1000 ng/ml to 10 ng/ml in the presence of 4 ng/ml BMP15, the significant stimulatory effect on thymidine incorporation was maintained. However, when oGDF9 concentrations were held constant at 1000 ng/ml but oBMP15 was diluted from 4 ng/ml to 0.04 ng/ml, the significant stimulation of thymidine incorporation was only observed when oBMP15 concentrations were >2 ng/ml (n = 6 independent pools of granulosa cells, data not shown).
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). oBMP15 stimulated thymidine incorporation at both doses used and the addition of either murine or ovine GDF9 to oBMP15 stimulated thymidine incorporation, but the overall values obtained were similar to those for equivalent concentrations of oBMP15 alone (Fig. 1). When oGDF9 was serially diluted from 1000 ng/ml to 10 ng/ml in the presence of 4 ng/ml BMP15, the significant stimulatory effect was maintained at all dilutions. When oGDF9 was held constant at 1000 ng/ml but oBMP15 diluted from 4 ng/ml to 0.04 ng/ml, the significant stimulation of thymidine incorporation was only observed at the 4 ng/ml dose (n = 3 independent pools of granulosa cells, data not shown).
Progesterone production
Sheep
mGDF9 stimulated progesterone production from ovine granulosa cells whereas oGDF9 was inhibitory. oBMP15 did not affect progesterone production on its own (Fig. 2). The addition of oBMP15 at 4 ng/ml did not alter or modify the affects of 1000 ng/ml of mGDF9 (P = 0.98) or oGDF9 (P = 0.92) when either were added alone (Fig. 2). When oGDF9 was serially diluted from 1000 ng/ml to 10 ng/ml in the presence of 4 ng/ml BMP15, the significant suppressive effects on progesterone were observed at GDF9 concentrations >200 ng/ml whereas when oGDF9 was held constant at 1000 ng/ml, the significant suppressive effect was lost when BMP15 was diluted below 4 ng/ml (n = 6 independent pools of granulosa cells, data not shown).
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). Addition of oBMP15 at 8 ng/ml but not 4 ng/ml also inhibited progesterone production (Fig. 2). In contrast to the lack of effect observed with the low concentrations of either GDF9 or BMP15 alone, progesterone production was significantly suppressed when these two factors were added together. Dilution of either GDF9 from 1000 ng/ml or BMP15 from 4 ng/ml caused a loss in significant suppression of progesterone (n = 6 independent pools of granulosa cells, data not shown).
Inhibin production
Sheep
mGDF9 inhibited whereas oGDF9 stimulated inhibin production (Fig. 3). oBMP15 did not affect inhibin production, although it appeared to block the inhibitory affects of mGDF9. There was no discernable co-operation between oGDF9 and oBMP15 (Fig. 3).
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Discussion |
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In the present study, oBMP15 stimulated thymidine incorporation in ovine and bovine granulosa cells. This is consistent with the finding that hBMP15 stimulates thymidine incorporation in rat and human granulosa cells (Otsuka et al. 2000, Di Pasquale et al. 2004). However, using the same batch preparation as described herein, oBMP15 did not stimulate 3H-thymidine incorporation in rat granulosa cells (McNatty et al. 2005). These data are also consistent with the previously stated hypothesis for GDF9, that the functions of the BMP15 may vary between species of origin of granulosa cells. Moreover, the question as to whether this could, in part, be due to the species of origin of the growth factor is another variable that remains to be answered.
As we have reported for rat granulosa cells, a synergistic effect of GDF9 and BMP15 was observed with respect to thymidine incorporation in ovine granulosa cells, whereas in bovine cells the combined effects of ovine or murine GDF9 and oBMP15 were not different from those of BMP15 alone. Of interest was the finding that oBMP15 was able to neutralize the inhibitory effects of mGDF9 in bovine as well as in ovine granulosa cells. Taken together, these data support the hypothesis that GDF9 and BMP15 co-operate to regulate cell proliferation in granulosa cells. In general, the mean stimulatory effects of mGDF9 + oBMP15 or oGDF9 + oBMP15 on thymidine incorporation by ruminant granulosa cells were relatively small (i.e. 1.2–1.6-fold) compared with those observed in rats (6.5–7.0-fold; see McNatty et al. 2005). This, in part, might be related to the proliferation rates of granulosa cells in rodents and ruminants as assessed from the times taken for follicles to grow from the primordial/primary stages to ovulation (i.e. 20–35 days in rodents and 120–170 days in ruminants; Peters and McNatty 1980, Driancourt et al. 1993, Hunter et al. 2004).
In ovine granulosa cells, mGDF9 stimulated, whereas oGDF9 inhibited, FSH-stimulated progesterone production. In bovine granulosa cells, mGDF9 had no effect, whereas the highest dose of oGDF9 was inhibitory. The inhibition of progesterone by oGDF9 was similar to the effects observed by Vitt et al.(2000) where rat GDF9 caused a dose-dependent decrease in FSH-stimulated progesterone production in rat granulosa cells from either diethyl stilbestrol (DES) or gonadotrophin treated animals and by Yamamoto et al.(2002) who showed that rat GDF9 caused a dose-dependent decrease in 8-bromo cAMP-stimulated production in human granulosa cells. However, the present results are in contrast to those by Elvin et al.(1999) and McNatty et al.(2005) who showed a lack of interaction between mGDF9 and FSH in regulating progesterone production by mouse and rat granulosa cells. Collectively these data suggest that GDF9 differentially affects granulosa cell function in different species. Moreover, it seems likely that the differential effects are related to both the species of origin of the granulosa cells and species of origin of the growth factor.
Compared with data for GDF9, there are relatively few reports on the effects of BMP15 with respect to steroid production in different species. In the present study BMP15 alone did not affect FSH-stimulated production by ovine granulosa cells but at the highest dose suppressed production by bovine cells. Previous studies report that hBMP15 suppressed FSH-stimulated progesterone production by rat granulosa cells (Otsuka et al. 2000). When ovine or murine GDF9 and oBMP15 were added together to bovine granulosa cells, progesterone production was suppressed to a greater level than that observed for either growth factor alone. Moreover, the suppressive effects of mGDF9 plus oBMP15 or oGDF9 plus oBMP15 were greater than additive indicating that these growth factors co-operate in bovine cells. This finding is similar to that found for GDF9 and BMP15 in regulating progesterone production in rat (McNatty et al. 2005). However, no such co-operative effect was observed between these growth factors in regulating progesterone production in ovine granulosa cells.
In previous studies evaluating the role of GDF9 on inhibin production, rat GDF9 stimulated granulosa cells from rats or humans (Hayashi et al. 1999, Roh et al. 2003, Kaivo-Oja et al. 2003), whereas no effects were observed with either murine or ovine GDF9 on rat granulosa cells (McNatty et al. 2005). In the present study, mGDF9 alone inhibited inhibin production from ovine and bovine granulosa cells, whereas oGDF9 increased inhibin production in ovine but not bovine granulosa cells. A large part of these differences may be attributable to the assays used to measure inhibin, the maturational stage of the granulosa cells and/or the culture conditions employed. However, it is important to note that mGDF9 and oGDF9 had opposite effects on inhibin production when tested side by side in the same pools of ovine granulosa cells. Thus, the species of origin of GDF9 may also account for some of the observed differences. Consistent with our previous data with rat granulosa cells (McNatty et al. 2005), oBMP15 did not appear to regulate inhibin production in either ovine or bovine granulosa cells. However, in contrast to the strong synergistic effects between GDF9 and BMP15 in regulating -inhibin production reported for the rat (McNatty et al. 2005), no co-operative effects were apparent for either ovine or bovine granulosa cells. Collectively, these data for inhibin show that the effects of GDF9 and BMP15 in vitro appear to be dependent upon the species of granulosa cells used for the assay and the species of origin of the growth factor. These suggest that species specificity of the growth factors may be regulated both at the target cell and by the structure of the growth factor itself. It is also possible that some of the differences observed in these studies are in part due to the different maturational states of the granulosa cells.
In sheep and cows, GDF9 mRNA and/or protein is present in oocytes of most, if not all, follicles at all stages of growth including primordial follicles (Bodensteiner et al. 1999). The present results are consistent with the notion that GDF9 alone may not be mitogenic in ruminant granulosa cells. It seems more likely, based on the in vitro evidence, that in sheep, but not cattle, GDF9 potentiates, in some way, the proliferative effects of BMP15 on granulosa cells. In sheep, BMP15 is present in oocytes of follicles from the primary stage onwards. Moreover, in sheep lacking active BMP15 (Galloway et al. 2000) or immunized against BMP15 or GDF9 (Juengel et al. 2002), follicular growth is arrested from the primary stage of development. The ontogeny of BMP15 expression in cattle is currently unknown. Nevertheless, the present in vitro findings are consistent with BMP15 alone being a key mitogenic factor during ovarian follicular development in ruminants.
In ruminants, BMPs are considered to be important luteinization inhibitors in granulosa cells during ovarian follicular development (Knight and Glister 2003, Monget et al. 2002). The present results for sheep suggest that GDF9 but not BMP15 is an important luteinization inhibitor, whereas for cattle both GDF9 and BMP15 contribute to suppressing progesterone.
Interestingly, while the effects of either of the growth factors alone were often divergent between species, the overall effects of both growth factors together in each species appear to be similar (current study and McNatty et al. 2005). These effects are indicative of a growth factor complex that stimulates cell proliferation and inhibits gonadotrophin-induced differentiation. An exception to this relates to the effects of mGDF9 with oBMP15 on progesterone production from ovine granulosa cells but this is unlikely to be physiologically relevant.
In conclusion, the effects of GDF9 and BMP15 in vitro appear dependent not only on the species of cell used for the assay, but also on the species of origin of the growth factor, indicating that the target cell and the structure of the growth factor itself both have an influence on the biological effects that were observed. These findings suggest some caution is needed when extrapolating findings from in vitro bioassays from one species to another. Given that GDF9 and BMP15 are likely to be present throughout most stages of follicular growth in sheep and cattle, it is suggested that these oocyte-secreted factors should be considered as an important functional signaling unit rather than as individual paracrine reagents acting independent of one another.
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Footnotes |
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Supported by New Zealand Foundation for Research, Science and Technology, the Royal Society of New Zealand Marsden Fund, Ovita Limited, Dunedin, New Zealand and Sigrid Juselius Foundation.
Received 7 October 2004
First decision 12 November 2004
Accepted 17 December 2004
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References |
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 R. B. Gilchrist, L. J. Ritter, S. Myllymaa, N. Kaivo-Oja, R. A. Dragovic, T. E. Hickey, O. Ritvos, and D. G. Mottershead Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation J. Cell Sci., September 15, 2006; 119(18): 3811 - 3821. [Abstract] [Full Text] [PDF]
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L J Spicer, P Y Aad, D Allen, S Mazerbourg, and A J Hsueh Growth differentiation factor-9 has divergent effects on proliferation and steroidogenesis of bovine granulosa cells. J. Endocrinol., May 1, 2006; 189(2): 329 - 339. [Abstract] [Full Text] [PDF]
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 J. L Juengel, K. L Reader, A. H Bibby, S. Lun, I. Ross, L. J Haydon, and K. P McNatty The role of bone morphogenetic proteins 2, 4, 6 and 7 during ovarian follicular development in sheep: contrast to rat. Reproduction, March 1, 2006; 131(3): 501 - 513. [Abstract] [Full Text] [PDF]
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E. Clelland, G. Kohli, R. K. Campbell, S. Sharma, S. Shimasaki, and C. Peng Bone Morphogenetic Protein-15 in the Zebrafish Ovary: Complementary Deoxyribonucleic Acid Cloning, Genomic Organization, Tissue Distribution, and Role in Oocyte Maturation Endocrinology, January 1, 2006; 147(1): 201 - 209. [Abstract] [Full Text] [PDF]
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M. K. Skinner Regulation of primordial follicle assembly and development Hum. Reprod. Update, September 1, 2005; 11(5): 461 - 471. [Abstract] [Full Text] [PDF]
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