scholarly journals Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function

Reproduction ◽  
2005 ◽  
Vol 129 (4) ◽  
pp. 473-480 ◽  
Author(s):  
Kenneth P McNatty ◽  
Jennifer L Juengel ◽  
Karen L Reader ◽  
Stan Lun ◽  
Samu Myllymaa ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Granulosa Cells ◽  
Thymidine Incorporation ◽  
Progesterone Production ◽  
Differentiation Factor ◽  
Morphogenetic Protein ◽  
Growth Differentiation Factor 9 ◽  
Bone Morphogenetic Protein 15

The oocyte-secreted polypeptide growth factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15, also known as GDF9B) have both been shown to be essential for ovarian follicular growth and function. The effects of murine (m) and ovine (o) GDF9 as well as oBMP15, alone or together, on 3H-thymidine uptake and progesterone and inhibin production by granulosa cells from rats were determined. Murine GDF9 stimulated thymidine incorporation by granulosa cells whereas oGDF9 and oBMP15 alone had no effect. However, oBMP15 given together with mGDF9 or oGDF9 was very potent in stimulating 3H-thymidine incorporation by granulosa cells with a greater than 3-fold stimulation compared with any growth factor alone. The synergistic effect of oBMP15 and oGDF9 was almost completely blocked by antibodies generated against these growth factors when administered either alone or in combination. While neither GDF9 (murine or ovine) nor oBMP15 were able to modulate FSH-stimulated progesterone production on their own, FSH-stimulated progesterone production by granulosa cells was potently inhibited when BMP15 and GDF9 were administered together. Immunoreactive α-inhibin levels increased more than 15-fold from granulosa cells when BMP15 and GDF9 were given together whereas consistent stimulatory effects of either growth factor alone were not observed. The effects of GDF9 and BMP15, when added together, were different than those observed for the growth factors alone. Therefore, we hypothesize that within the ovary, these oocyte-secreted growth factors co-operate to regulate proliferation and gonadotropin-induced differentiation of granulosa cells in mammals.

scholarly journals Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants

Reproduction ◽  
2005 ◽  
Vol 129 (4) ◽  
pp. 481-487 ◽  
Author(s):  
Kenneth P McNatty ◽  
Jennifer L Juengel ◽  
Karen L Reader ◽  
Stan Lun ◽  
Samu Myllymaa ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Granulosa Cells ◽  
Progesterone Production ◽  
Differentiation Factor ◽  
Morphogenetic Protein ◽  
Growth Differentiation Factor 9 ◽  
Bone Morphogenetic Protein 15

The oocyte-secreted polypeptide growth factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15, also known as GDF9B) have both been shown to be essential for ovarian follicular development and ovulation rate. In addition, it is known from both in vivo and in vitro studies that these factors co-operate in some manner. To date, most studies examining the in vitro effects of these growth factors have used the rodent model. However, the evidence suggests that these growth factors have somewhat different roles between rodents and ruminants. Therefore, the objectives of these studies were to examine the effects of GDF9 and BMP15, alone and together, on the functions of ovine and bovine granulosa cells under in vitro conditions. Ovine (o)BMP15 given together with murine (m)GDF9 or oGDF9 was more potent in stimulating 3H-thymidine incorporation by ovine granulosa cells compared with each growth factor alone. For bovine granulosa cells, there appeared to be little or no co-operativity between oBMP15 and oGDF9 as oBMP15 alone was as potent as any combination of the two growth factors in stimulating 3H-thymidine uptake. The species of origin of GDF9 affected the progesterone response in ovine granulosa cells with mGDF9 stimulating and oGDF9 inhibiting progesterone production. Ovine BMP15 alone had no effect on progesterone production by ovine granulosa cells and these growth factors did not appear to co-operate. FSH-stimulated progesterone production by bovine granulosa cells was most potently inhibited when oBMP15 and murine or ovine GDF9 were administered together. As was observed for progesterone, the species of origin of GDF9 affected inhibin production by ovine granulosa cells where mGDF9 inhibited while oGDF9 stimulated production. Murine GDF9 also inhibited inhibin production from bovine granulosa cells. For both ovine and bovine granulosa cells, BMP15 alone had no effect on inhibin production and there did not appear to be any co-operation between GDF9 and BMP15. These results indicate that the effects of BMP15 and GDF9 varied with respect to the species of origin of the growth factor. Moreover, the effects of GDF9 and BMP15 together were often co-operative and not always the same as those observed for these growth factors alone.

Signalling pathways involved in the synergistic effects of human growth differentiation factor 9 and bone morphogenetic protein 15

2016 ◽  
Vol 28 (4) ◽  
pp. 491 ◽  
Author(s):  
Karen L. Reader ◽  
David G. Mottershead ◽  
Georgia A. Martin ◽  
Robert B. Gilchrist ◽  
Derek A. Heath ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bone Morphogenetic Protein ◽  
Granulosa Cell ◽  
Thymidine Incorporation ◽  
Signalling Pathways ◽  
Differentiation Factor ◽  
Morphogenetic Protein ◽  
Growth Differentiation Factor 9 ◽  
Bone Morphogenetic Protein 15 ◽  
Stimulation Of

Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) act synergistically to regulate granulosa cell proliferation and steroid production in several species. Several non-Sma and mothers against decapentaplegic (SMAD) signalling pathways are involved in the action of murine and ovine GDF9 and BMP15 in combination, with the pathways utilised differing between the two species. The aims of this research were to determine if human GDF9 and BMP15 also act in a synergistic manner to stimulate granulosa cell proliferation and to identify which non-SMAD signalling pathways are activated. Human GDF9 with BMP15 (GDF9 + BMP15) stimulated an increase in 3H-thymidine incorporation (P < 0.001), which was greater than the increase with BMP15 alone, while GDF9 alone had no effect. The stimulation of 3H-thymidine incorporation by GDF9 + BMP15 was reduced by the addition of inhibitors to the SMAD2/3, nuclear factor-KB (NF-KB) and c-Jun N-terminal kinase (JNK) signalling pathways. Inhibitors to the SMAD1/5/8, extracellular signal-regulated kinase mitogen-activated protein kinase (ERK-MAPK) or p38-MAPK pathways had no effect. The addition of the BMP receptor 2 (BMPR2) extracellular domain also inhibited stimulation of 3H-thymidine incorporation by GDF9 + BMP15. In conclusion, human GDF9 and BMP15 act synergistically to stimulate granulosa cell proliferation, a response that also involves species-specific non-SMAD signalling pathways.

134. EPIDERMAL GROWTH FACTOR RECEPTOR/MAPK3/1 PATHWAY CROSS-TALK ENABLES GROWTH DIFFERENTIATION FACTOR 9 TO SIGNAL THROUGH SMAD2/3 IN MOUSE GRANULOSA CELLS

2009 ◽  
Vol 21 (9) ◽  
pp. 53
Author(s):  
M. Sasseville ◽  
L. J. Ritter ◽  
T. Nguyen ◽  
D. G. Mottershead ◽  
D. L. Russell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Granulosa Cells ◽  
Cross Talk ◽  
Egf Receptor ◽  
Thymidine Incorporation ◽  
Differentiation Factor ◽  
Growth Differentiation Factor 9 ◽  
Epidermal Growth ◽  
Receptor Inhibitor

Oocyte-secreted growth differentiation factor 9 (GDF9) plays a critical role throughout folliculogenesis. It has been shown to control many functions of granulosa cells, including gene expression, steroidogenesis and proliferation. This study investigates the cellular requirements that allow GDF9 to act on granulosa cells. Our results showed that GDF9 (20 ng/ml)-stimulated mouse granulosa cells 3H-thymidine incorporation was inhibited by a type 1 receptor Alk4/5/7 inhibitor (SB431542, 5 μM), by an epidermal growth factor (EGF) receptor inhibitor (AG1478, 5μM) and a MEK1 inhibitor (U0126, 10 μM). Interestingly, activin A- and TGFβ-stimulated 3H-thymidine incorporation shared similar inhibitor sensitivity. Moreover, when denuded oocytes were used as the mitogenic agent, SB431542, AG1478 and U0126 all prevented the increase in 3H-thymidine incorporation. Oocyte-stimulated 3H-thymidine incorporation in secondary follicles and cumulus-oocyte complexes were also sensitive to Alk4/5/7, EGF receptor and MEK1 inhibition. Basal and EGF-stimulated levels of phopho-MAPK3/1 were inhibited by using the EGF receptor inhibitor, but were not affected by inhibition of Alk4/5/7 or by adding GDF9 in granulosa cells. Using granulosa cells transfected with a SMAD3-luciferase reporter construct, GDF9-stimulated SMAD3 response could be inhibited by Alk4/5/7, EGFR and MEK1 inhibitors. Genes involved in cumulus cells expansion (Ptx3 and Has2) were upregulated in granulosa cells by co-culturing with denuded oocytes and that upregulation was inhibited by Alk4/5/7 as well as by EGF receptor inhibition. These results suggest that TGFβ superfamily members signalling through Smad2/3 share a common requirement of EGF receptor-dependant phospho-MAPK3/1 throughout folliculogenesis. These results strongly suggest that, apart from its role in the transmission of the ovulatory LH signal within the ovarian follicle, EGF receptor pathway might serve as modulators of GDF9 action on granulosa cells. Hence the interaction between endocrine and oocyte signalling may be mediated at the level of MAPK and Smad2/3 cross-talk in granulosa cells.

Sign in / Sign up

Export Citation Format

Share Document