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Growth differentiation factor-9 signaling in the ovary
Molecular and Cellular Endocrinology 202 (2003) 31 /36 www.elsevier.com/locate/mce
Growth differentiation factor-9 signaling in the ovary S. Mazerbourg, A.J.W. Hsueh * Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305-5317, USA
Abstract Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the transforming growth factor-b (TGF-b) superfamily. In GDF-9 null mice, follicle development is arrested at the primary stage and in vivo treatment with GDF-9 enhances the progression of primordial and primary follicles into small preantral follicles. In vitro, GDF-9 promotes granulosa cell proliferation but inhibits FSH-induced differentiation. GDF-9 also promotes the differentiation of theca cells in vivo and in vitro. GDF-9, like TGF-b or activin, is a close member of the bone morphogenetic proteins (BMPs) family. GDF-9 likely initiates signaling by assembling two related but distinct types of receptors, both of which are serine/threonine kinases with a single transmembrane domain. The ligand /receptor binding activates intracellular transcription factors called Smads. In granulosa cells, Vitt et al. have shown that the BMP receptor type II is involved in GDF-9 signaling. The type I receptors and the Smad pathway for GDF-9 remain to be identified. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: GDF-9; Follicle development; BMP receptors; Activin receptors
Development of the mammalian ovary is characterized by the endowment of a fixed number of primordial follicles throughout fetal life. The pool of primordial follicles is gradually depleted during reproductive life. The follicles develop through primordial, primary, and preantral stages before acquiring an antral cavity (McGee and Hsueh, 2000). Follicular growth and differentiation are controlled by pituitary gonadotrophins as well as paracrine factors produced by granulosa and theca cells (Adashi, 1994). Many studies have indicated that the oocyte contributes to the stimulation of granulosa cell growth as well as the modulation of granulosa cell differentiation (Buccione et al., 1990; Coskun et al., 1995; Vanderhyden et al., 1992; Vanderhyden and Tonary, 1995). The paracrine signaling factors produced by the oocyte that regulate follicle development are not well characterized. Interestingly, the growth differentiation factor-9 (GDF-9) secreted by the oocyte has been shown to play a key role in follicular development: GDF-9-deficient mice display an arrest of follicle growth at the primary follicular stage (Dong et al., 1996). Thus, GDF-9 was the first oocyte-derived
* Corresponding author. Tel.: /1-650-725-6802; fax: /1-650-7257102. E-mail address: [email protected] (A.J.W. Hsueh).
growth factor shown to be required for ovarian somatic cell function.
1. The role of GDF-9 on ovarian functions 1.1. GDF-9 in follicular development The expression of GDF-9 mRNA and protein is confined to the oocyte of primary and larger follicles in rats (Hayashi et al., 1999; Jaatinen et al., 1999), mice (Dong et al., 1996; McGrath et al., 1995), and humans (Aaltonen et al., 1999). In ovine and bovine ovaries, GDF-9 mRNA is found in primordial follicles as well (Bodensteiner et al., 1999). Mutant mice with a deletion of the GDF-9 gene have demonstrated the important role of this oocyte factor in the stimulation of early follicular growth (Dong et al., 1996). Subsequently, Vitt et al. have shown that recombinant GDF-9 is able to stimulate initial follicle recruitment in vivo (Vitt et al., 2000a). Treatment with recombinant GDF-9 for 7 days (days 5/12 of age) or for 10 days (days 5/15 of age) in immature female rats augmented ovarian weight and led to an increase in the number of primary and small preantral follicles after 10 days of treatment by 30 and 60%, respectively. Concomitantly, the number of pri-
0303-7207/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0303-7207(03)00058-3
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mordial follicles was decreased by 29%, but the number of large preantral follicles was not affected. Although treatment with FSH also increased ovarian weight, FSH increased the number of small and large preantral follicles by 36 and 177%, but did not influence the number of primary and primordial follicles. Thus, GDF-9 specifically increased the number of primary and small preantral follicles (Vitt et al., 2000a) in contrast to FSH that mainly stimulates preantral follicular growth (McGee et al., 1997). Furthermore, in vitro, GDF-9 promotes the survival as well as the progression of human follicles to the secondary stage after 7 days in organ culture (Hreinsson et al., 2002). Finally, GDF-9 appears to be essential for folliculogenesis at the primary-preantral follicle transition. 1.2. Effects of GDF-9 on cultured granulosa and theca cell function GDF-9 has been shown to play a role in granulosa cell differentiation in small antral and preovulatory follicles. In studies using cultured granulosa cells derived from early antral and preovulatory rat follicles, GDF-9 promotes granulosa cell proliferation as reflected by increases in thymidine incorporation, but inhibits FSHinduced steroidogenesis and LH receptor expression (Vitt et al., 2000b). Furthermore, Roh et al. recently have shown that treatment with GDF-9 stimulates dosedependent increases of both inhibin A and inhibin B production (Roh et al., 2003). Cotreatment with FSH led to synergistic increases in inhibin production despite the inhibitory effects of GDF-9 on FSH-induced estrogen production and LH receptor formation (Vitt et al., 2000b). Therefore, GDF-9 produced by the oocytes of antral follicles could stimulate the production of inhibins that, in turn, regulate pituitary FSH secretion. Treatment with GDF-9 alone also enhances FSHinduced cumulus expansion, cyclooygenase 2 and steroidogenic acute regulator protein mRNA expression (Elvin et al., 1999a) as well as progesterone production in cultured granulosa cells (Elvin et al., 1999a, 2000; Vitt et al., 2000b) Theca cells are also the target of GDF-9. In GDF-9 null mice, the follicular theca layer is absent (Dong et al., 1996). This was confirmed by the absence of expression of selective theca cell markers such as cytochrome P450 17,20 lyase (CYP17), LH receptor, and c-kit mRNA (Elvin et al., 1999b). Furthermore, the in vivo application of GDF-9 led to an increase in ovarian CYP17 content (Vitt et al., 2000a). Finally, primary theca cells have been shown to be responsive to GDF-9, thus, androstenedione production was increased by GDF-9 in primary cultures of theca cells (Solovyeva et al., 2000). These results are consistent with the hypothesis that GDF-9 could directly regulate theca cell differentiation in vivo.
The GDF-9 effects on ovarian cells have been investigated in different species in vitro and in vivo, however, the receptors as well as the intracellular pathway mediating these effects are still unknown.
2. GDF-9 signaling pathway in granulosa cells 2.1. GDF-9 and GDF-9B/BMP-15: homo- or heterodimer GDF-9 was discovered from mouse genomic DNA by PCR using degenerated oligonucleotides corresponding to conserved regions of known transforming growth factor-b (TGF-b) family members (McPherron and Lee, 1993). GDF-9 is a member of the cystine knot protein group and belongs to the TGF-b superfamily (McPherron and Lee, 1993; Vitt et al., 2001). A characteristic feature of this group is the presence of six conserved cysteine residues involved in the formation of the knot. The cystine knot forces the protein to adapt a threedimensional arrangement that in part exposes hydrophobic residues to the aqueous surface of the protein. These hydrophobic residues facilitate the formation of homo- or hetero-dimers. TGF-b, activins, and bone morphogenetic protein (BMPs) have an additional cysteine residue that strengthens dimerization by forming a covalent disulfide bridge between the two subunits of the dimer (Vitt et al., 2001). Interestingly, GDF-9 lacks this additional cysteine leaving unanswered whether GDF-9 may function as a monomer or a noncovalently-linked dimer. If GDF-9 functions as a noncovalently-linked dimer, it could associate with its closest paralog, GDF-9B/ BMP-15, also lacking the additional cysteine residue (Vitt et al., 2002). Both GDF-9 and GDF-9B/BMP-15 are synthesized by the oocyte of primary follicles in rodents (Dube et al., 1998; Laitinen et al., 1998; Otsuka et al., 2000), humans (Aaltonen et al., 1999), and sheep (Galloway et al., 2000). Like GDF-9, GDF-9B/BMP-15 stimulates rat granulosa proliferation and inhibits FSHinduced progesterone secretion (Otsuka et al., 2001, 2000). In Inverdale sheep with the homozygous GDF9B/BMP-15 gene mutation (XI/XI), defective initial follicle recruitment was detected as evidenced by the blockage of follicle development beyond the primary stage (Galloway et al., 2000). In sheep, this phenotype is similar to the phenotype of GDF9 / mice whereas GDF-9B / mice are subfertile but not infertile (Yan et al., 2001). These data may suggest that GDF-9B/BMP15 is more essential in sheep whereas GDF-9 is more essential in rodents. As both are present, we can also propose that variation in the ratio of homodimers (GDF-9 or GDF-9B)/heterodimers (GDF-9/GDF-9B) could influence follicular development. In Inverdale sheep, inactivation of one copy of GDF-9B/BMP-15
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(XI/X/) increased the ovulation rate (Galloway et al., 2000). It is possible that either a decreased production of GDF-9B homodimers or an increased production of GDF-9/GDF-9B heterodimers could lead to lower inhibin production with a resultant increase in FSH secretion. Although serum FSH levels have not been measured in the heterozygous Inverdale sheep, an increased FSH level is consistent with the observed high fecundity observed in these animals and could explain the twinning phenotype. 2.2. The TGF-b/activin/BMP signaling pathway Members of the TGF-b superfamily have been shown to initiate signaling by assembling receptor complexes that activate Smad transcription factors (Kawabata et al., 1998; Massague, 1998). The ligand brings together members from two families of receptor serine/threonine kinases, known as the type I and type II receptors (Fig. 1 and Table 1). Two general models of ligand binding have been observed (Fig. 1). One model involves direct binding to the type II receptor and subsequent interaction of this complex with the type I receptor that in
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effect becomes recruited into the complex. This binding mode is characteristic of TGF-b and activin receptors (Attisano et al., 1992; Mathews and Vale, 1991; Wrana et al., 1992). The second binding model is typical of BMP receptors and is cooperative, involving type I and type II receptors that bind ligands with high affinity when expressed together but low affinity when expressed separately (Rosenzweig et al., 1995; ten Dijke et al., 1994). Within the receptor complex, the type II receptor phosphorylates the type I receptor in a glycine- and serine-rich motif just upstream of the kinase domain. This region, termed the GS domain, is important in controlling type I receptor kinase function, and its phosphorylation activates the receptor type I kinase, which subsequently initiates the downstream Smad signaling pathways. The receptor-regulated Smads (RSmads) are direct targets of the type I receptor kinase and are phosphorylated on a conserved carboxylterminal SSXS motif. Thus, Smad-2 and Smad-3 are phosphorylated by TGF-b and activin receptors while Smad-1, -5, and -8 are activated by BMP receptors. Once phosphorylated, the R-Smads form heteromeric complexes with the common mediator, the co-Smad-4.
Fig. 1. Schematic representation of the TGF-b BMPs, and GDF-9 signaling pathways. TGF-b and BMPs bind to two types of serine /threonine receptors, termed type I (Rc type I) and type II (Rc type II). BMP type I receptors bind BMP directly whereas the TGF-b activin type I receptor does not bind ligands in the absence of the TGF-b activin type II receptor. GDF-9 binds to the BMP type II receptor directly; the type I receptor is unknown. Formation of the tetramer receptor (2 type I/2 type II) allows the phosphorylation of the type I receptor by the type II receptor on the GS domain resulting in activation of the type I receptor kinase ((1) (2)). The type I receptors specifically recognize and phosphorylate the R-Smads (3). R-Smads associate with a common co-Smad, Smad-4 (4). Both R-Smads and the co-Smad in the complex may participate in DNA binding on Smad binding elements (SBE) and recruitment of transcriptional cofactors (5). The intracellular pathway induced by GDF-9 remains to be elucidated.
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Table 1 Ligands, receptors, and Smads involved in TGF- superfamily signaling pathways Ligands
Receptor type I
Receptor type II
R-Smads
Co-Smad
TGF-b
ALK-1
TR-II?
Smad-1/-5/-8
Smad-4
BMP-6/-7 AMH
ALK-2 (ActR-I) ALK-2 (ActR-I)
ActR-II/-IIB AMHR-II
Smad-1/-5/-8
Smad-4
BMP-2/-4/-7 BMP-2/-4/-7 GDF-5 AMH
ALK-3 (BMPR-IA) ALK-6 (BMPR-IB) ALK-6 (BMPR-IB)
BMPR-II BMPR-II AMHR-II
Smad-1/-5/-8
Smad-4
Activin TGF-b Nodal
ALK-4 (ActR-IB) ALK-5 (TR-I) ALK-7
ActR-II/-IIB TR-II ActR-IIB
Smad-2/-3
Smad-4
GDF-9 GDF-9B/BMP-15
?
BMPR-II BMPR-II?
?
Smad-4?
Five distinct type II and seven type I receptors have been identified. Five R-Smads share one co-Smad, Smad-4. Except for the receptor type II, the different components of the GDF-9 pathway are unknown. ActR, activin receptor; BMPR, BMP receptor; TR, TGF-b receptor.
The R-Smad/co-Smad-4 complex then translocates to the nucleus to regulate gene expression. Smads can positively or negatively modulate the transcriptional activity by recruiting coactivators or corepressors, respectively (Massague and Chen, 2000a; Massague and Wotton, 2000b). 2.3. The GDF-9 signaling pathway GDF-9 is most closely related to GDF-9B/BMP-15. This subgroup of TGF-b-related proteins is intermediate between the BMPs and the activin/TGF-b ligands but closer to the BMPs (Newfeld et al., 1999; Vitt et al., 2002). As for GDF-9, the receptors of GDF-9B/BMP-15 remain to be identified. BMP-2 and -4 have been shown to interact with ALK-3/BMPR-IA, ALK-6/BMPR-IB, and BMPR type II (Kawabata et al., 1998; Koenig et al., 1994; Liu et al., 1995; Nohno et al., 1995; Rosenzweig et al., 1995; Yamaji et al., 1994) (Table 1). In addition to interacting with these BMP receptors, BMP-7 can also signal through activin type I (ALK-2) and activin type II receptors (Liu et al., 1995; Yamashita et al., 1994). All of these receptors are expressed in granulosa cells (Drummond et al., 2002; Shimasaki et al., 1999; Sidis et al., 1998). As previously described, BMP receptors type I and type II are able to bind their ligands without coexpression. Thus, the BMP-4 biological activity has been dose-dependently abolished by a soluble form of a BMP type I receptor (Natsume et al., 1997). Similarly, the soluble form of the BMP receptor type I and type II (the ectodomain of the receptor fused to the Fc-binding region of human IgG) was screened for potential to interact with GDF-9. Our recent data have shown the effects of GDF-9, on both granulosa cell proliferation and progesterone production, can be blocked completely by the extracellular domain of BMP receptor type II (BMPR-II). Activin receptor type II as well as ALK-3 and ALK-6 are equally potent in reducing GDF-9
effects by approximately 30%, whereas the effect of ALK-2 is only about 15%. Similarly, BMPR-II is capable of completely restoring FSH-induced progesterone production thus preventing the effect of GDF-9. To further confirm the direct interactions between GDF-9 and the ectodomains of different BMP receptors, Vitt et al. have also shown that GDF-9 was successfully immunoprecipitated by the extracellular domain of BMPR-II (Vitt et al., 2002). In contrast, the activin receptor type II was only minimally efficient in binding GDF-9 whereas none of the type I receptors had a significant effect. Finally, the inhibition of BMPR-II biosynthesis completely blocked GDF-9 action on the proliferation and differentiation of rat granulosa cells in vitro (Fig. 2). Thus, these different results show that
Fig. 2. Inhibition of BMPR-II biosynthesis suppresses GDF-9 signaling in cultured granulosa cells. Addition of BMPR-II morpholino antisense oligomers dose-dependently inhibited GDF-9 stimulation of thymidine incorporation by cultured rat granulosa cells. In contrast, addition of different doses of control morpholino did not affect GDF9 action. CT, control samples without morpholino. Asterisks indicate the first dose of each dose /response curve at which a significant inhibitory effect was observed. Reproduction with permission from Vitt et al. (2002)).
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BMPR-II is one of the receptors involved in the signaling pathway of GDF-9 in granulosa cells (Table 1). Nevertheless, activin receptor type II cannot be excluded as a second potential receptor type II with a weaker affinity for GDF-9. Activin receptor type II, which has the highest affinity for activin, also binds BMP-7 and BMP-2 (Yamashita et al., 1994). Concerning the receptor type I, even if ALK-3 and ALK-6 are able to partially block GDF-9 activity, binding to GDF9 may be weak and these receptors cannot be immunoprecipitated with GDF-9. From these results, we can propose two hypotheses: (1) GDF-9 needs to be bound to the receptor type II before interacting with the type I (similar to the TGF-b/activin model). (2) ALK-3 and ALK-6 are not the receptors type I with the highest affinity for GDF-9. Confirming the importance of BMPR-II in GDF-9 signaling and identifying the receptor type I and the Smads involved will be the next steps in the investigation.
3. Conclusion GDF-9 is an oocyte-derived factor required for granulosa and theca cell function in vivo. It has been shown to enhance primordial and primary follicle growth and play a role in somatic cell function at multiple stages of follicular development. GDF-9 is most closely related to GDF-9B/BMP-15. Whether GDF-9 and GDF-9B/BMP-15 function as a homodimer or heterodimer remains to be determined. Most of the elements of the GDF-9 signal transduction cascade are still unknown. Vitt et al. have recently shown that BMPR-II is a receptor type II involved in GDF-9 signaling. Further identification of the receptor type I of GDF-9 and of the Smad pathway involved in granulosa cells is of interest.
Acknowledgements We thank Caren Spencer for editorial assistance.
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morphogenetic protein system in the ovary. Proc. Natl. Acad. Sci. USA 96, 7282 /7287. Sidis, Y., Fujiwara, T., Leykin, L., Isaacson, K., Toth, T., Schneyer, A.L., 1998. Characterization of inhibin/activin subunit, activin receptor, and follistatin messenger ribonucleic acid in human and mouse oocytes: evidence for activin’s paracrine signaling from granulosa cells to oocytes. Biol. Reprod. 59, 807 /812. Solovyeva, E.V., Hayashi, M., Margi, K., Barkats, C., Klein, C., Amsterdam, A., Hsueh, A.J., Tsafriri, A., 2000. Growth differentiation factor-9 stimulates rat theca-interstitial cell androgen biosynthesis. Biol. Reprod. 63, 1214 /1218. ten Dijke, P., Yamashita, H., Sampath, T.K., Reddi, A.H., Estevez, M., Riddle, D.L., Ichijo, H., Heldin, C.H., Miyazono, K., 1994. Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J. Biol. Chem. 269, 16985 /16988. Vanderhyden, B.C., Telfer, E.E., Eppig, J.J., 1992. Mouse oocytes promote proliferation of granulosa cells from preantral and antral follicles in vitro. Biol. Reprod. 46, 1196 /1204. Vanderhyden, B.C., Tonary, A.M., 1995. Differential regulation of progesterone and estradiol production by mouse cumulus and mural granulosa cells by A factor(s) secreted by the oocyte. Biol. Reprod. 53, 1243 /1250. Vitt, U.A., Hayashi, M., Klein, C., Hsueh, A.J., 2000b. Growth differentiation factor-9 stimulates proliferation but suppresses the follicle-stimulating hormone-induced differentiation of cultured granulosa cells from small antral and preovulatory rat follicles. Biol. Reprod. 62, 370 /377. Vitt, U.A., Hsu, S.Y., Hsueh, A.J., 2001. Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol. Endocrinol. 15, 681 /694. Vitt, U.A., Mazerbourg, S., Klein, C., Hsueh, A.J.W., 2002. Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol. Reprod. 67, 473 /480. Vitt, U.A., McGee, E.A., Hayashi, M., Hsueh, A.J., 2000a. In vivo treatment with GDF-9 stimulates primordial and primary follicle progression and theca cell marker CYP17 in ovaries of immature rats. Endocrinology 141, 3814 /3820. Wrana, J.L., Attisano, L., Carcamo, J., Zentella, A., Doody, J., Laiho, M., Wang, X.F., Massague, J., 1992. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003 /1014. Yamaji, N., Celeste, A.J., Thies, R.S., Song, J.J., Bernier, S.M., Goltzman, D., Lyons, K.M., Nove, J., Rosen, V., Wozney, J.M., 1994. A mammalian serine/threonine kinase receptor specifically binds BMP-2 and BMP-4. Biochem. Biophys. Res. Commun. 205, 1944 /1951. Yamashita, H., ten Dijke, P., Franzen, P., Miyazono, K., Heldin, C.H., 1994. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J. Biol. Chem. 269, 20172 /20178. Yan, C., Wang, P., DeMayo, J., DeMayo, F.J., Elvin, J.A., Carino, C., Prasad, S.V., Skinner, S.S., Dunbar, B.S., Dube, J.L., Celeste, A.J., Matzuk, M.M., 2001. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol. Endocrinol. 15, 854 /866.
Growth differentiation factor-9 signaling in the ovary S. Mazerbourg, A.J.W. Hsueh * Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305-5317, USA
Abstract Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the transforming growth factor-b (TGF-b) superfamily. In GDF-9 null mice, follicle development is arrested at the primary stage and in vivo treatment with GDF-9 enhances the progression of primordial and primary follicles into small preantral follicles. In vitro, GDF-9 promotes granulosa cell proliferation but inhibits FSH-induced differentiation. GDF-9 also promotes the differentiation of theca cells in vivo and in vitro. GDF-9, like TGF-b or activin, is a close member of the bone morphogenetic proteins (BMPs) family. GDF-9 likely initiates signaling by assembling two related but distinct types of receptors, both of which are serine/threonine kinases with a single transmembrane domain. The ligand /receptor binding activates intracellular transcription factors called Smads. In granulosa cells, Vitt et al. have shown that the BMP receptor type II is involved in GDF-9 signaling. The type I receptors and the Smad pathway for GDF-9 remain to be identified. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: GDF-9; Follicle development; BMP receptors; Activin receptors
Development of the mammalian ovary is characterized by the endowment of a fixed number of primordial follicles throughout fetal life. The pool of primordial follicles is gradually depleted during reproductive life. The follicles develop through primordial, primary, and preantral stages before acquiring an antral cavity (McGee and Hsueh, 2000). Follicular growth and differentiation are controlled by pituitary gonadotrophins as well as paracrine factors produced by granulosa and theca cells (Adashi, 1994). Many studies have indicated that the oocyte contributes to the stimulation of granulosa cell growth as well as the modulation of granulosa cell differentiation (Buccione et al., 1990; Coskun et al., 1995; Vanderhyden et al., 1992; Vanderhyden and Tonary, 1995). The paracrine signaling factors produced by the oocyte that regulate follicle development are not well characterized. Interestingly, the growth differentiation factor-9 (GDF-9) secreted by the oocyte has been shown to play a key role in follicular development: GDF-9-deficient mice display an arrest of follicle growth at the primary follicular stage (Dong et al., 1996). Thus, GDF-9 was the first oocyte-derived
* Corresponding author. Tel.: /1-650-725-6802; fax: /1-650-7257102. E-mail address: [email protected] (A.J.W. Hsueh).
growth factor shown to be required for ovarian somatic cell function.
1. The role of GDF-9 on ovarian functions 1.1. GDF-9 in follicular development The expression of GDF-9 mRNA and protein is confined to the oocyte of primary and larger follicles in rats (Hayashi et al., 1999; Jaatinen et al., 1999), mice (Dong et al., 1996; McGrath et al., 1995), and humans (Aaltonen et al., 1999). In ovine and bovine ovaries, GDF-9 mRNA is found in primordial follicles as well (Bodensteiner et al., 1999). Mutant mice with a deletion of the GDF-9 gene have demonstrated the important role of this oocyte factor in the stimulation of early follicular growth (Dong et al., 1996). Subsequently, Vitt et al. have shown that recombinant GDF-9 is able to stimulate initial follicle recruitment in vivo (Vitt et al., 2000a). Treatment with recombinant GDF-9 for 7 days (days 5/12 of age) or for 10 days (days 5/15 of age) in immature female rats augmented ovarian weight and led to an increase in the number of primary and small preantral follicles after 10 days of treatment by 30 and 60%, respectively. Concomitantly, the number of pri-
0303-7207/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0303-7207(03)00058-3
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mordial follicles was decreased by 29%, but the number of large preantral follicles was not affected. Although treatment with FSH also increased ovarian weight, FSH increased the number of small and large preantral follicles by 36 and 177%, but did not influence the number of primary and primordial follicles. Thus, GDF-9 specifically increased the number of primary and small preantral follicles (Vitt et al., 2000a) in contrast to FSH that mainly stimulates preantral follicular growth (McGee et al., 1997). Furthermore, in vitro, GDF-9 promotes the survival as well as the progression of human follicles to the secondary stage after 7 days in organ culture (Hreinsson et al., 2002). Finally, GDF-9 appears to be essential for folliculogenesis at the primary-preantral follicle transition. 1.2. Effects of GDF-9 on cultured granulosa and theca cell function GDF-9 has been shown to play a role in granulosa cell differentiation in small antral and preovulatory follicles. In studies using cultured granulosa cells derived from early antral and preovulatory rat follicles, GDF-9 promotes granulosa cell proliferation as reflected by increases in thymidine incorporation, but inhibits FSHinduced steroidogenesis and LH receptor expression (Vitt et al., 2000b). Furthermore, Roh et al. recently have shown that treatment with GDF-9 stimulates dosedependent increases of both inhibin A and inhibin B production (Roh et al., 2003). Cotreatment with FSH led to synergistic increases in inhibin production despite the inhibitory effects of GDF-9 on FSH-induced estrogen production and LH receptor formation (Vitt et al., 2000b). Therefore, GDF-9 produced by the oocytes of antral follicles could stimulate the production of inhibins that, in turn, regulate pituitary FSH secretion. Treatment with GDF-9 alone also enhances FSHinduced cumulus expansion, cyclooygenase 2 and steroidogenic acute regulator protein mRNA expression (Elvin et al., 1999a) as well as progesterone production in cultured granulosa cells (Elvin et al., 1999a, 2000; Vitt et al., 2000b) Theca cells are also the target of GDF-9. In GDF-9 null mice, the follicular theca layer is absent (Dong et al., 1996). This was confirmed by the absence of expression of selective theca cell markers such as cytochrome P450 17,20 lyase (CYP17), LH receptor, and c-kit mRNA (Elvin et al., 1999b). Furthermore, the in vivo application of GDF-9 led to an increase in ovarian CYP17 content (Vitt et al., 2000a). Finally, primary theca cells have been shown to be responsive to GDF-9, thus, androstenedione production was increased by GDF-9 in primary cultures of theca cells (Solovyeva et al., 2000). These results are consistent with the hypothesis that GDF-9 could directly regulate theca cell differentiation in vivo.
The GDF-9 effects on ovarian cells have been investigated in different species in vitro and in vivo, however, the receptors as well as the intracellular pathway mediating these effects are still unknown.
2. GDF-9 signaling pathway in granulosa cells 2.1. GDF-9 and GDF-9B/BMP-15: homo- or heterodimer GDF-9 was discovered from mouse genomic DNA by PCR using degenerated oligonucleotides corresponding to conserved regions of known transforming growth factor-b (TGF-b) family members (McPherron and Lee, 1993). GDF-9 is a member of the cystine knot protein group and belongs to the TGF-b superfamily (McPherron and Lee, 1993; Vitt et al., 2001). A characteristic feature of this group is the presence of six conserved cysteine residues involved in the formation of the knot. The cystine knot forces the protein to adapt a threedimensional arrangement that in part exposes hydrophobic residues to the aqueous surface of the protein. These hydrophobic residues facilitate the formation of homo- or hetero-dimers. TGF-b, activins, and bone morphogenetic protein (BMPs) have an additional cysteine residue that strengthens dimerization by forming a covalent disulfide bridge between the two subunits of the dimer (Vitt et al., 2001). Interestingly, GDF-9 lacks this additional cysteine leaving unanswered whether GDF-9 may function as a monomer or a noncovalently-linked dimer. If GDF-9 functions as a noncovalently-linked dimer, it could associate with its closest paralog, GDF-9B/ BMP-15, also lacking the additional cysteine residue (Vitt et al., 2002). Both GDF-9 and GDF-9B/BMP-15 are synthesized by the oocyte of primary follicles in rodents (Dube et al., 1998; Laitinen et al., 1998; Otsuka et al., 2000), humans (Aaltonen et al., 1999), and sheep (Galloway et al., 2000). Like GDF-9, GDF-9B/BMP-15 stimulates rat granulosa proliferation and inhibits FSHinduced progesterone secretion (Otsuka et al., 2001, 2000). In Inverdale sheep with the homozygous GDF9B/BMP-15 gene mutation (XI/XI), defective initial follicle recruitment was detected as evidenced by the blockage of follicle development beyond the primary stage (Galloway et al., 2000). In sheep, this phenotype is similar to the phenotype of GDF9 / mice whereas GDF-9B / mice are subfertile but not infertile (Yan et al., 2001). These data may suggest that GDF-9B/BMP15 is more essential in sheep whereas GDF-9 is more essential in rodents. As both are present, we can also propose that variation in the ratio of homodimers (GDF-9 or GDF-9B)/heterodimers (GDF-9/GDF-9B) could influence follicular development. In Inverdale sheep, inactivation of one copy of GDF-9B/BMP-15
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(XI/X/) increased the ovulation rate (Galloway et al., 2000). It is possible that either a decreased production of GDF-9B homodimers or an increased production of GDF-9/GDF-9B heterodimers could lead to lower inhibin production with a resultant increase in FSH secretion. Although serum FSH levels have not been measured in the heterozygous Inverdale sheep, an increased FSH level is consistent with the observed high fecundity observed in these animals and could explain the twinning phenotype. 2.2. The TGF-b/activin/BMP signaling pathway Members of the TGF-b superfamily have been shown to initiate signaling by assembling receptor complexes that activate Smad transcription factors (Kawabata et al., 1998; Massague, 1998). The ligand brings together members from two families of receptor serine/threonine kinases, known as the type I and type II receptors (Fig. 1 and Table 1). Two general models of ligand binding have been observed (Fig. 1). One model involves direct binding to the type II receptor and subsequent interaction of this complex with the type I receptor that in
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effect becomes recruited into the complex. This binding mode is characteristic of TGF-b and activin receptors (Attisano et al., 1992; Mathews and Vale, 1991; Wrana et al., 1992). The second binding model is typical of BMP receptors and is cooperative, involving type I and type II receptors that bind ligands with high affinity when expressed together but low affinity when expressed separately (Rosenzweig et al., 1995; ten Dijke et al., 1994). Within the receptor complex, the type II receptor phosphorylates the type I receptor in a glycine- and serine-rich motif just upstream of the kinase domain. This region, termed the GS domain, is important in controlling type I receptor kinase function, and its phosphorylation activates the receptor type I kinase, which subsequently initiates the downstream Smad signaling pathways. The receptor-regulated Smads (RSmads) are direct targets of the type I receptor kinase and are phosphorylated on a conserved carboxylterminal SSXS motif. Thus, Smad-2 and Smad-3 are phosphorylated by TGF-b and activin receptors while Smad-1, -5, and -8 are activated by BMP receptors. Once phosphorylated, the R-Smads form heteromeric complexes with the common mediator, the co-Smad-4.
Fig. 1. Schematic representation of the TGF-b BMPs, and GDF-9 signaling pathways. TGF-b and BMPs bind to two types of serine /threonine receptors, termed type I (Rc type I) and type II (Rc type II). BMP type I receptors bind BMP directly whereas the TGF-b activin type I receptor does not bind ligands in the absence of the TGF-b activin type II receptor. GDF-9 binds to the BMP type II receptor directly; the type I receptor is unknown. Formation of the tetramer receptor (2 type I/2 type II) allows the phosphorylation of the type I receptor by the type II receptor on the GS domain resulting in activation of the type I receptor kinase ((1) (2)). The type I receptors specifically recognize and phosphorylate the R-Smads (3). R-Smads associate with a common co-Smad, Smad-4 (4). Both R-Smads and the co-Smad in the complex may participate in DNA binding on Smad binding elements (SBE) and recruitment of transcriptional cofactors (5). The intracellular pathway induced by GDF-9 remains to be elucidated.
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Table 1 Ligands, receptors, and Smads involved in TGF- superfamily signaling pathways Ligands
Receptor type I
Receptor type II
R-Smads
Co-Smad
TGF-b
ALK-1
TR-II?
Smad-1/-5/-8
Smad-4
BMP-6/-7 AMH
ALK-2 (ActR-I) ALK-2 (ActR-I)
ActR-II/-IIB AMHR-II
Smad-1/-5/-8
Smad-4
BMP-2/-4/-7 BMP-2/-4/-7 GDF-5 AMH
ALK-3 (BMPR-IA) ALK-6 (BMPR-IB) ALK-6 (BMPR-IB)
BMPR-II BMPR-II AMHR-II
Smad-1/-5/-8
Smad-4
Activin TGF-b Nodal
ALK-4 (ActR-IB) ALK-5 (TR-I) ALK-7
ActR-II/-IIB TR-II ActR-IIB
Smad-2/-3
Smad-4
GDF-9 GDF-9B/BMP-15
?
BMPR-II BMPR-II?
?
Smad-4?
Five distinct type II and seven type I receptors have been identified. Five R-Smads share one co-Smad, Smad-4. Except for the receptor type II, the different components of the GDF-9 pathway are unknown. ActR, activin receptor; BMPR, BMP receptor; TR, TGF-b receptor.
The R-Smad/co-Smad-4 complex then translocates to the nucleus to regulate gene expression. Smads can positively or negatively modulate the transcriptional activity by recruiting coactivators or corepressors, respectively (Massague and Chen, 2000a; Massague and Wotton, 2000b). 2.3. The GDF-9 signaling pathway GDF-9 is most closely related to GDF-9B/BMP-15. This subgroup of TGF-b-related proteins is intermediate between the BMPs and the activin/TGF-b ligands but closer to the BMPs (Newfeld et al., 1999; Vitt et al., 2002). As for GDF-9, the receptors of GDF-9B/BMP-15 remain to be identified. BMP-2 and -4 have been shown to interact with ALK-3/BMPR-IA, ALK-6/BMPR-IB, and BMPR type II (Kawabata et al., 1998; Koenig et al., 1994; Liu et al., 1995; Nohno et al., 1995; Rosenzweig et al., 1995; Yamaji et al., 1994) (Table 1). In addition to interacting with these BMP receptors, BMP-7 can also signal through activin type I (ALK-2) and activin type II receptors (Liu et al., 1995; Yamashita et al., 1994). All of these receptors are expressed in granulosa cells (Drummond et al., 2002; Shimasaki et al., 1999; Sidis et al., 1998). As previously described, BMP receptors type I and type II are able to bind their ligands without coexpression. Thus, the BMP-4 biological activity has been dose-dependently abolished by a soluble form of a BMP type I receptor (Natsume et al., 1997). Similarly, the soluble form of the BMP receptor type I and type II (the ectodomain of the receptor fused to the Fc-binding region of human IgG) was screened for potential to interact with GDF-9. Our recent data have shown the effects of GDF-9, on both granulosa cell proliferation and progesterone production, can be blocked completely by the extracellular domain of BMP receptor type II (BMPR-II). Activin receptor type II as well as ALK-3 and ALK-6 are equally potent in reducing GDF-9
effects by approximately 30%, whereas the effect of ALK-2 is only about 15%. Similarly, BMPR-II is capable of completely restoring FSH-induced progesterone production thus preventing the effect of GDF-9. To further confirm the direct interactions between GDF-9 and the ectodomains of different BMP receptors, Vitt et al. have also shown that GDF-9 was successfully immunoprecipitated by the extracellular domain of BMPR-II (Vitt et al., 2002). In contrast, the activin receptor type II was only minimally efficient in binding GDF-9 whereas none of the type I receptors had a significant effect. Finally, the inhibition of BMPR-II biosynthesis completely blocked GDF-9 action on the proliferation and differentiation of rat granulosa cells in vitro (Fig. 2). Thus, these different results show that
Fig. 2. Inhibition of BMPR-II biosynthesis suppresses GDF-9 signaling in cultured granulosa cells. Addition of BMPR-II morpholino antisense oligomers dose-dependently inhibited GDF-9 stimulation of thymidine incorporation by cultured rat granulosa cells. In contrast, addition of different doses of control morpholino did not affect GDF9 action. CT, control samples without morpholino. Asterisks indicate the first dose of each dose /response curve at which a significant inhibitory effect was observed. Reproduction with permission from Vitt et al. (2002)).
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BMPR-II is one of the receptors involved in the signaling pathway of GDF-9 in granulosa cells (Table 1). Nevertheless, activin receptor type II cannot be excluded as a second potential receptor type II with a weaker affinity for GDF-9. Activin receptor type II, which has the highest affinity for activin, also binds BMP-7 and BMP-2 (Yamashita et al., 1994). Concerning the receptor type I, even if ALK-3 and ALK-6 are able to partially block GDF-9 activity, binding to GDF9 may be weak and these receptors cannot be immunoprecipitated with GDF-9. From these results, we can propose two hypotheses: (1) GDF-9 needs to be bound to the receptor type II before interacting with the type I (similar to the TGF-b/activin model). (2) ALK-3 and ALK-6 are not the receptors type I with the highest affinity for GDF-9. Confirming the importance of BMPR-II in GDF-9 signaling and identifying the receptor type I and the Smads involved will be the next steps in the investigation.
3. Conclusion GDF-9 is an oocyte-derived factor required for granulosa and theca cell function in vivo. It has been shown to enhance primordial and primary follicle growth and play a role in somatic cell function at multiple stages of follicular development. GDF-9 is most closely related to GDF-9B/BMP-15. Whether GDF-9 and GDF-9B/BMP-15 function as a homodimer or heterodimer remains to be determined. Most of the elements of the GDF-9 signal transduction cascade are still unknown. Vitt et al. have recently shown that BMPR-II is a receptor type II involved in GDF-9 signaling. Further identification of the receptor type I of GDF-9 and of the Smad pathway involved in granulosa cells is of interest.
Acknowledgements We thank Caren Spencer for editorial assistance.
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