Growth differentiation factor-9
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Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.
Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function. Growth differentiation factor-9 (GDF9) is expressed in oocytes and is thought to be required for ovarian folliculogenesis. GDF9 is a member of the transforming growth factor-beta (TGFβ) superfamily.
Growth Differentiation Factor 9 (GDF9)
Growth differentiation factor 9 (GDF9) is an oocyte derived growth factor in the transforming growth factor ß (TGF-ß) superfamily. It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells. Paracrine interactions between the developing oocyte and its surrounding follicular cells is essential for the correct progression of both the follicle and the oocyte. GDF9 is essential for the overall process of folliculogenesis, oogenesis and ovulation and thus plays a major role in female fertility.
GDF9 acts through two receptors on the cells surrounding the oocyte, it binds to bone morphogenic protein receptor 2 (BMPRII) and downstream to this utilizes the TGF-ß receptor type 1 (ALK5). Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins. SMAD proteins are transcription factors found in vertebrates, insects and nematodes, and are the intercellular substrates of all TGF-ß molecules. GDF9 specifically activates SMAD2 and SMAD3 which form a complex with SMAD4, a common partner of all SMAD proteins, that is then able to translocate to the nucleus to regulate gene expression.
Role in Folliculogenesis
Early Follicle Development
In many mammalian species GDF9 is essential for early follicular development through its direct action on the granulosa cells allowing proliferation and differentiation  The deletion of ‘’Gdf9’’ results in decreased ovary size, halted follicular development at the stage of the primary follicle and the absence of any corpus lutea. The proliferative ability of granulosa cells is significantly reduced whereby no more than a single layer of granulosa cells is able to surround and thus support the developing oocyte. Any somatic cell formation after the primary layer is atypical and asymmetrical. Normally the follicle becomes atretic and degenerates although this does not occur emphasizing the abnormality of these supporting cells. GDF9 deficiency is further linked with the up regulation of inhibin. The normal expression of GDF9 allows the downregulation of inhibin a and thus promotes the ability of the follicle to progress past the primary stage of development.
In vitro exposure of mammalian ovarian tissue to GDF9 promotes primary follicle progression. GDF9 stimulates growth of preantral follicles by preventing granulosa cell apoptosis. This may occur through increased follicle stimulating hormone (FSH) receptor expression or be a result of post-receptor signaling.
Some sheep breeds show a range of fertility phenotypes due to eight single nucleotide polymorphisms (SNP) across the coding region of GDF9. A SNP in the Gdf9 gene resulting in a non conservative amino acid change was identified, whereby ewes homozygous for the SNP were infertile and completely lacked any follicle growth.
Late Follicle Development
Typical of later stages of follicle development is the appearance of cumulus cells. GDF9 causes the expansion of cumulus cells, a characteristic process in normal follicular development. GDF9 induces hyaluronanic synthase 2 (Has2) and suppresses urokinase plasminogen activator (uPA) mRNA synthesis in granulosa cells. This allows an extracellular matrix rich in hyaluronic acid, allowing the expansion of cumulus cells. Silencing of GDF9 expression results in the absence of cumulus cell expansion, this highlights the integral role of GDF9 signaling in altering granulosa cell enzymes and therefore allowing cumulus cell expansion in late stages of folliculogenesis.
Role in Oogenesis and Ovulation
Role in Oogenesis
A lack of GDF9 causes pathophysiological alterations in the oocyte itself in addition to severe follicular abnormality. Oocytes reach normal size and form a zona pellucida although organelles become clustered and cortical granules do not form. In GDF9 deficient oocytes the meiotic ability is significantly altered, where less than half will proceed metaphase 1 or 2 and a large percentage of oocytes have abnormal germinal vesicle breakdown. As cumulus cells surround the oocyte during development and remain with the oocyte once it is ovulated, GDF9 expression in cumulus cells is important in allowing an ideal oocyte microenvironment. The altered phenotype observed in GDF9 deficient oocytes likely results from the lack off somatic cell input in later stages of folliculogenesis.
Role in Ovulation
GDF9 is required just prior to the surge of luteinizing hormone (LH), a key event responsible for ovulation. Prior to the LH surge, GDF9 supports the metabolic function of cumulus cells, allowing glycolysis and cholesterol biosynthesis. Cholesterol is a precursor of many essential steroid hormones such as progesterone. Progesterone levels rise significantly post ovulation to support the early stages of embryogenesis. In preovulatory follicles, GDF9 promotes the production of progesterone via the stimulation of the prostaglandin- EP2 receptor signaling pathway.
Altered GDF9 Expression in Humans
Mutations in GDF9
GDF9 mutations are present in women with premature ovarian failure, in addition to mothers of dizygotic twins. Three particular missense mutations GDF9 P103S, GDF9 P374L and GDF9 R454C have been found, although GDF9 P103S is present in women with dizygotic twins as well as women with premature ovarian failure. Given the same mutation is linked with a poly ovulatory phenotype and the failure of ovulation, these mutations are thought to alter the rate of ovulation, rather than specifically increasing or decreasing the rate. Most of these mutations are located in the pro-region of the gene that encodes GDF9, an area essential for the dimerization and hence activation of the encoded protein.
Link with Polycystic Ovarian Syndrome (PCOS)
PCOS accounts for approximately 90% of anovulation infertility, affecting 5-10% of woman of reproductive age. In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS. In particular, levels of GDF9 increase as the follicle develops from primordial stages to more mature stages. Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis. GDF9 expression is not only reduced in women with PCOS but also delayed. Despite these facts the exact link of GDF9 with PCOS is not well established.
Bone morphogenic protein 15 (BMP15) is highly expressed in the oocyte and the surrounding follicular cells contributing greatly to folliculogenesis and oogenesis. Like GDF9, BMP15 belongs to the TGF-ß superfamily. Differences in the synergistic action of BMP15 and GDF9 appear to be species dependent. BMP15 and GDF9 act in an additive manner to increase mitotic proliferation in sheep granulosa cells, although the same effect is not observed in bovine granulosa cells. The silencing of ‘’Bmp15’’ in mice results in partial fertility but normal histological appearance of the ovary. Although, when this is combined with the silencing of one allele of ‘’Gdf9’’, mice are completely infertile due to insufficient folliculogenesis and altered cumulus cell morphology. Mice with this genome also fail to release oocytes resulting in trapped oocytes in the corpus lutea. This phenotype is absent in ‘’Gdf9’’ silenced mice and only present a small population of ‘’Bmp15’’ silenced mice. This reveals the synergistic relationship of GDF9 and BMP15 whereby the silencing of both genes results in more severe outcome then either of the genes alone. It is thought that any co operative effects of GDF9 and BMP15 are modulated through the BMPRII receptor.
GDF9 plays an important role in the development of primary follicles in the ovary. It has a critical role in granulosa cell and theca cell growth, as well as in differentiation and maturation of the oocyte.
GDF9 has been connected to differences in ovulation rate and in premature cessation of ovary function, therefore has a significant role in fertility.
The cell surface receptor through which GDF9 generates a signal is the bone morphogenetic protein type II receptor (BMPR2).
- ↑ McGrath SA, Esquela AF, Lee SJ (Jun 1995). "Oocyte-specific expression of growth/differentiation factor-9". Mol Endocrinol. 9 (1): 131–6. doi:10.1210/me.9.1.131. PMID 7760846.
- ↑ 2.0 2.1 "Entrez Gene: GDF9 growth differentiation factor 9".
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Otsuka, F., McTavish, K. and Shimasaki, S. (2011). Integral role of GDF-9 and BMP-15 in ovarian function. Mol. Reprod. Dev., 78(1), pp.9-21
- ↑ 4.0 4.1 4.2 4.3 Castro, F., Cruz, M. and Leal, C. (2015). Role of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Ovarian Function and Their Importance in Mammalian Female Fertility — A Review. Asian Australas. J. Anim. Sci, 29(8), pp.1065-1074
- ↑ 5.0 5.1 Gilchrist, R., Lane, M. and Thompson, J. (2008). Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Human Reproduction Update, 14(2), pp.159-177
- ↑ Huang, Q., Cheung, A., Zhang, Y., Huang, H., Auersperg, N. and Leung, P. (2009). Effects of growth differentiation factor 9 on cell cycle regulators and ERK42/44 in human granulosa cell proliferation. AJP: Endocrinology and Metabolism, 296(6), pp.E1344-E1353
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Dong, J., Albertini, D., Nishimori, K., Kumar, T., Lu, N. and Matzuk, M. (1996). Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature, 383(6600), pp.531-535
- ↑ Elvin, J., Yan, C., Wang, P., Nishimori, K. and Matzuk, M. (1999). Molecular Characterization of the Follicle Defects in the Growth Differentiation Factor 9-Deficient Ovary. Molecular Endocrinology, 13(6), pp.1018-1034
- ↑ 9.0 9.1 Hreinsson, J., Scott, J., Rasmussen, C., Swahn, M., Hsueh, A. and Hovatta, O. (2002). Growth Differentiation Factor-9 Promotes the Growth, Development, and Survival of Human Ovarian Follicles in Organ Culture. The Journal of Clinical Endocrinology & Metabolism, 87(1), pp.316-321
- ↑ Nilsson, E. (2002). Growth and Differentiation Factor-9 Stimulates Progression of Early Primary but Not Primordial Rat Ovarian Follicle Development. Biology of Reproduction, 67(3), pp.1018-1024
- ↑ Orisaka, M., Orisaka, S., Jiang, J., Craig, J., Wang, Y., Kotsuji, F. and Tsang, B. (2006). Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage. Molecular Endocrinology, 20(10), pp.2456-2468
- ↑ Hanrahan, J. (2003). Mutations in the Genes for Oocyte-Derived Growth Factors GDF9 and BMP15 Are Associated with Both Increased Ovulation Rate and Sterility in Cambridge and Belclare Sheep (Ovis aries). Biology of Reproduction, 70(4), pp.900-909
- ↑ Nicol, L., Bishop, S., Pong-Wong, R., Bendixen, C., Holm, L., Rhind, S. and McNeilly, A. (2009). Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. Reproduction, 138(6), pp.921-933
- ↑ 14.0 14.1 14.2 14.3 Elvin, J., Clark, A., Wang, P., Wolfman, N. and Matzuk, M. (1999). Paracrine Actions Of Growth Differentiation Factor-9 in the Mammalian Ovary. Molecular Endocrinology, 13(6), pp.1035-1048
- ↑ Zhao, H., Qin, Y., Kovanci, E., Simpson, J., Chen, Z. and Rajkovic, A. (2007). Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertility and Sterility, 88(5), pp.1474-1476
- ↑ Gui, L. (2005). RNA Interference Evidence That Growth Differentiation Factor-9 Mediates Oocyte Regulation of Cumulus Expansion in Mice. Biology of Reproduction, 72(1), pp.195-199
- ↑ Sugiura, K., Pendola, F. and Eppig, J. (2005). Oocyte control of metabolic cooperativity between oocytes and companion granulosa cells: energy metabolism. Developmental Biology, 279(1), pp.20-30
- ↑ Elvin, J., Yan, C. and Matzuk, M. (2000). Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway. Proceedings of the National Academy of Sciences, 97(18), pp.10288-10293
- ↑ 19.0 19.1 19.2 19.3 19.4 Yan, C., Wang, P., DeMayo, J., DeMayo, F., Elvin, J., Carino, C., Prasad, S., Skinner, S., Dunbar, B., Dube, J., Celeste, A. and Matzuk, M. (2001). Synergistic Roles of Bone Morphogenetic Protein 15 and Growth Differentiation Factor 9 in Ovarian Function. Molecular Endocrinology, 15(6), pp.854-866
- ↑ Laissue, P. (2006). Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European Journal of Endocrinology, 154(5), pp.739-744
- ↑ Shimasaki, S., Moore, R., Otsuka, F. and Erickson, G. (2004). The Bone Morphogenetic Protein System In Mammalian Reproduction. Endocrine Reviews, 25(1), pp.72-101
- ↑ de Resende, L., Vireque, A., Santana, L., Moreno, D., de Sá Rosa e Silva, A., Ferriani, R., Scrideli, C. and Reis, R. (2012). Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. Journal of Assisted Reproduction and Genetics, 29(10), pp.1057-1065
- ↑ 23.0 23.1 23.2 Wei, L., Huang, R., Li, L., Fang, C., Li, Y. and Liang, X. (2014). Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics, 31(11), pp.1483-1490
- ↑ McNatty, K., Juengel, J., Reader, K., Lun, S., Myllymaa, S., Lawrence, S., Western, A., Meerasahib, M., Mottershead, D., Groome, N., Ritvos, O. and Laitinen, M. (2005). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction, 129(4), pp.481-487
- ↑ Edwards, S., Reader, K., Lun, S., Western, A., Lawrence, S., McNatty, K. and Juengel, J. (2008). The Cooperative Effect of Growth and Differentiation Factor-9 and Bone Morphogenetic Protein (BMP)-15 on Granulosa Cell Function Is Modulated Primarily through BMP Receptor II. Endocrinology, 149(3), pp.1026-1030
- ↑ Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K (2004). "Physiology of GDF9 and BMP15 signalling molecules". Anim Reprod Sci. 82-83: 447–60. doi:10.1016/j.anireprosci.2004.04.021. PMID 15271472.
- ↑ Su Y, Wu X, O'Brien M, Pendola F, Denegre J, Matzuk M, Eppig J (2004). "Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop". Dev Biol. 276 (1): 64–73. doi:10.1016/j.ydbio.2004.08.020. PMID 15531364.
- ↑ McNatty K, Hudson N, Whiting L, Reader K, Lun S, Western A, Heath D, Smith P, Moore L, Juengel J (2007). "The Effects of Immunizing Sheep with Different BMP15 or GDF9 Peptide Sequences on Ovarian Follicular Activity and Ovulation Rate". Biol Reprod. 76 (4): 552–60. doi:10.1095/biolreprod.106.054361. PMID 17093201.
- ↑ Juengel J, Hudson N, Whiting L, McNatty K (2004). "Effects of immunization against bone morphogenetic protein 15 and growth differentiation factor 9 on ovulation rate, fertilization, and pregnancy in ewes". Biol Reprod. 70 (3): 557–61. doi:10.1095/biolreprod.103.023333. PMID 14585806.
- ↑ Kovanci E, Rohozinski J, Simpson J, Heard M, Bishop C, Carson S (2007). "Growth differentiating factor-9 mutations may be associated with premature ovarian failure". Fertil Steril. 87 (1): 143–6. doi:10.1016/j.fertnstert.2006.05.079. PMID 17156781.
- ↑ Mazerbourg S, Hsueh A (2006). "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. 12 (4): 373–83. doi:10.1093/humupd/dml014. PMID 16603567.
- ↑ Vitt U, Mazerbourg S, Klein C, Hsueh A (2002). "Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9". Biol Reprod. 67 (2): 473–80. doi:10.1095/biolreprod67.2.473. PMID 12135884.
- McPherron AC, Lee SJ (1993). "GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines". J. Biol. Chem. 268 (5): 3444–9. PMID 8429021.
- Dong J, Albertini DF, Nishimori K, et al. (1996). "Growth differentiation factor-9 is required during early ovarian folliculogenesis". Nature. 383 (6600): 531–5. doi:10.1038/383531a0. PMID 8849725.
- Aaltonen J, Laitinen MP, Vuojolainen K, et al. (1999). "Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis". J. Clin. Endocrinol. Metab. 84 (8): 2744–50. doi:10.1210/jc.84.8.2744. PMID 10443672.
- Gilboa L, Nohe A, Geissendörfer T, et al. (2000). "Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors". Mol. Biol. Cell. 11 (3): 1023–35. doi:10.1091/mbc.11.3.1023. PMC 14828. PMID 10712517.
- Vitt UA, Mazerbourg S, Klein C, Hsueh AJ (2003). "Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9". Biol. Reprod. 67 (2): 473–80. doi:10.1095/biolreprod67.2.473. PMID 12135884.
- Liao WX, Moore RK, Otsuka F, Shimasaki S (2003). "Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9. Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep". J. Biol. Chem. 278 (6): 3713–9. doi:10.1074/jbc.M210598200. PMID 12446716.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Liao WX, Moore RK, Shimasaki S (2004). "Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9". J. Biol. Chem. 279 (17): 17391–6. doi:10.1074/jbc.M401050200. PMID 14970198.
- Schmutz J, Martin J, Terry A, et al. (2004). "The DNA sequence and comparative analysis of human chromosome 5". Nature. 431 (7006): 268–74. doi:10.1038/nature02919. PMID 15372022.
- Goehler H, Lalowski M, Stelzl U, et al. (2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Mol. Cell. 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Stelzl U, Worm U, Lalowski M, et al. (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070.
- Dixit H, Rao LK, Padmalatha V, et al. (2007). "Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure". Menopause. 12 (6): 749–54. doi:10.1097/01.gme.0000184424.96437.7a. PMID 16278619.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Laissue P, Christin-Maitre S, Touraine P, et al. (2006). "Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure". Eur. J. Endocrinol. 154 (5): 739–44. doi:10.1530/eje.1.02135. PMID 16645022.
- Palmer JS, Zhao ZZ, Hoekstra C, et al. (2007). "Novel variants in growth differentiation factor 9 in mothers of dizygotic twins". J. Clin. Endocrinol. Metab. 91 (11): 4713–6. doi:10.1210/jc.2006-0970. PMID 16954162.
- Chand AL, Ponnampalam AP, Harris SE, et al. (2006). "Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure". Fertil. Steril. 86 (4): 1009–12. doi:10.1016/j.fertnstert.2006.02.107. PMID 17027369.
- Kovanci E, Rohozinski J, Simpson JL, et al. (2007). "Growth differentiating factor-9 mutations may be associated with premature ovarian failure". Fertil. Steril. 87 (1): 143–6. doi:10.1016/j.fertnstert.2006.05.079. PMID 17156781.
- Hanavadi S, Martin TA, Watkins G, et al. (2007). "The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer". Ann. Surg. Oncol. 14 (7): 2159–66. doi:10.1245/s10434-007-9397-5. PMID 17453295.
- growth+differentiation+factor+9 at the US National Library of Medicine Medical Subject Headings (MeSH)