Growth differentiation factor-9: Difference between revisions

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'''Growth/differentiation factor 9''' is a [[protein]] that in humans is encoded by the ''GDF9'' [[gene]].<ref name="pmid7760846">{{cite journal |vauthors=McGrath SA, Esquela AF, Lee SJ | title = Oocyte-specific expression of growth/differentiation factor-9 | journal = Mol Endocrinol | volume = 9 | issue = 1 | pages = 131–6 |date=Jun 1995 | pmid = 7760846 | pmc =  | doi =10.1210/me.9.1.131 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GDF9 growth differentiation factor 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2661| accessdate = }}</ref>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Growth differentiation factor 9
| HGNCid = 4224
| Symbol = GDF9
| AltSymbols =;
| OMIM = 601918
| ECnumber = 
| Homologene = 3851
| MGIid = 95692
| GeneAtlas_image1 = PBB_GE_GDF9_221314_at_tn.png
| Function = {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}}
| Process = {{GNF_GO|id=GO:0007179 |text = transforming growth factor beta receptor signaling pathway}} {{GNF_GO|id=GO:0007292 |text = female gamete generation}}
  | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2661
    | Hs_Ensembl = ENSG00000164404
    | Hs_RefseqProtein = NP_005251
    | Hs_RefseqmRNA = NM_005260
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 132224772
    | Hs_GenLoc_end = 132228824
    | Hs_Uniprot = O60383
    | Mm_EntrezGene = 14566
    | Mm_Ensembl = ENSMUSG00000018238
    | Mm_RefseqmRNA = NM_008110
    | Mm_RefseqProtein = NP_032136
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 53276791
    | Mm_GenLoc_end = 53281323
    | Mm_Uniprot = Q3UWR9
  }}
}}
 
'''Growth differentiation factor 9''', also known as '''GDF9''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GDF9 growth differentiation factor 9| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2661| accessdate = }}</ref>


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{{PBB_Summary
{{PBB_Summary
| section_title =  
| section_title =  
| summary_text = 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 superfamily|transforming growth factor-beta (TGFβ) superfamily]].<ref name="entrez">{{cite web | title = Entrez Gene: GDF9 growth differentiation factor 9| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2661| accessdate = }}</ref>
| summary_text = 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 superfamily|transforming growth factor-beta (TGFβ) superfamily]].<ref name="entrez">{{cite web | title = Entrez Gene: GDF9 growth differentiation factor 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2661| accessdate = }}</ref>
}}
}}


GDF9 plays an important role in the development of primary [[Ovarian follicle|follicles]] in the [[ovary]].<ref>{{cite journal |author=Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K |title=Physiology of GDF9 and BMP15 signalling molecules |journal=Anim Reprod Sci |volume=82-83 |issue= |pages=447-60 |year= |pmid=15271472}}</ref> It has a critical role in [[granulosa cell]] and [[theca cell]] growth, as well as in differentiation and maturation of the oocyte.<ref>{{cite journal |author=Hreinsson J, Scott J, Rasmussen C, Swahn M, Hsueh A, Hovatta O |title=Growth differentiation factor-9 promotes the growth, development, and survival of human ovarian follicles in organ culture |journal=J Clin Endocrinol Metab |volume=87 |issue=1 |pages=316-21 |year=2002 |pmid=11788667}} [http://jcem.endojournals.org/cgi/content/abstract/87/1/316 link]</ref><ref>{{cite journal |author=Su Y, Wu X, O'Brien M, Pendola F, Denegre J, Matzuk M, Eppig J |title=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 |journal=Dev Biol |volume=276 |issue=1 |pages=64-73 |year=2004 |pmid=15531364}}</ref>
==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.<ref name="Otsuka_2011">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</ref> It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells.<ref name="Otsuka_2011" />  Paracrine interactions between the developing oocyte and its surrounding follicular cells is essential for the correct progression of both the follicle and the oocyte.<ref name="Castro_2015">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</ref> GDF9 is essential for the overall process of [[folliculogenesis]], [[oogenesis]] and [[ovulation]] and thus plays a major role in female fertility.<ref name="Castro_2015" />
 
==Signaling Pathway==
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).<ref name="Gilchrist_2008">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</ref> Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins.<ref name="Castro_2015" /> SMAD proteins are transcription factors found in vertebrates, insects and nematodes, and are the intercellular substrates of all TGF-ß molecules.<ref name=" Effects of growth differentiation factor 9 on cell cycle regulators and ERK42/44 in human granulosa cell proliferation."> 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</ref>  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.<ref name="Gilchrist_2008" />
 
==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 <ref name="Otsuka_2011" /> 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.<ref name="Dong_1996" >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</ref> 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.<ref name="Otsuka_2011" /> Any somatic cell formation after the primary layer is atypical and asymmetrical.<ref name="Dong_1996" />  Normally the follicle becomes atretic and degenerates although this does not occur emphasizing the abnormality of these supporting cells.<ref name="Dong_1996" /> GDF9 deficiency is further linked with the up regulation of inhibin.<ref name="Otsuka_2011" /> 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.<ref name=" Molecular Characterization of the Follicle Defects in the Growth Differentiation Factor 9-Deficient Ovary.">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</ref>


GDF9 has been connected to differences in [[ovulation]] rate<ref>{{cite journal |author=McNatty K, Hudson N, Whiting L, Reader K, Lun S, Western A, Heath D, Smith P, Moore L, Juengel J |title=The Effects of Immunizing Sheep with Different BMP15 or GDF9 Peptide Sequences on Ovarian Follicular Activity and Ovulation Rate |journal=Biol Reprod |volume= |issue= |pages= |year= |pmid=17093201}}</ref><ref>{{cite journal |author=Juengel J, Hudson N, Whiting L, McNatty K |title=Effects of immunization against bone morphogenetic protein 15 and growth differentiation factor 9 on ovulation rate, fertilization, and pregnancy in ewes |journal=Biol Reprod |volume=70 |issue=3 |pages=557-61 |year=2004 |pmid=14585806}}</ref> and in premature cessation of ovary function,<ref>{{cite journal |author=Kovanci E, Rohozinski J, Simpson J, Heard M, Bishop C, Carson S |title=Growth differentiating factor-9 mutations may be associated with premature ovarian failure |journal=Fertil Steril |volume=87 |issue=1 |pages=143-6 |year=2007 |pmid=17156781}}</ref> therefore has a significant role in [[fertility]].
''In vitro'' exposure of mammalian ovarian tissue to GDF9 promotes primary follicle progression.<ref name="Hreinsson_2002">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</ref><ref name=" Growth and Differentiation Factor-9 Stimulates Progression of Early Primary but Not Primordial Rat Ovarian Follicle Development.">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</ref> GDF9 stimulates growth of preantral follicles by preventing granulosa cell apoptosis.<ref name=" Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage.">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</ref> This may occur through increased follicle stimulating hormone (FSH) receptor expression or be a result of post-receptor signaling.<ref name="Otsuka_2011" />


The cell surface receptor through which GDF9 generates a signal is the [[bone morphogenetic protein]] type II receptor ([[BMPR2]]).<ref>{{cite journal |author=Mazerbourg S, Hsueh A |title=Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands |journal=Hum Reprod Update |volume=12 |issue=4 |pages=373-83 |year= |pmid=16603567}}</ref><ref>{{cite journal |author=Vitt U, Mazerbourg S, Klein C, Hsueh A |title=Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9 |journal=Biol Reprod |volume=67 |issue=2 |pages=473-80 |year=2002 |pmid=12135884}}</ref>
Some sheep breeds show a range of fertility phenotypes due to eight single nucleotide polymorphisms (SNP) across the coding region of GDF9.<ref name=" 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)." >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</ref> 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.<ref name=" Homozygosity for a single base-pair mutation in the oocyte-specific ''GDF9'' gene results in sterility in Thoka sheep.">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</ref>
 
===Late Follicle Development===
 
Typical of later stages of follicle development is the appearance of [[cumulus cells]].<ref name="Elvin_1999b">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</ref>  GDF9 causes the expansion of cumulus cells, a characteristic process in normal follicular development.<ref name="Castro_2015" /> GDF9 induces hyaluronanic synthase 2 (Has2) and suppresses urokinase plasminogen activator (uPA) mRNA synthesis in granulosa cells.<ref name="Elvin_1999b" /> This allows an extracellular matrix rich in hyaluronic acid, allowing the expansion of cumulus cells.<ref name=" Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure.">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</ref> 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.<ref name="Elvin_1999b" /><ref name=" RNA Interference Evidence That Growth Differentiation Factor-9 Mediates Oocyte Regulation of Cumulus Expansion in Mice.">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</ref>
 
==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.<ref name="Dong_1996" /> 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.<ref name="Dong_1996" /> 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.<ref name="Elvin_1999b" /> The altered phenotype observed in GDF9 deficient oocytes likely results from the lack off somatic cell input in later stages of folliculogenesis.<ref name="Dong_1996" />
 
===Role in Ovulation===
 
GDF9 is required just prior to the surge of [[luteinizing hormone]] (LH), a key event responsible for ovulation.<ref name="Otsuka_2011" /> Prior to the LH surge, GDF9 supports the metabolic function of cumulus cells, allowing glycolysis and cholesterol biosynthesis.<ref name=" Oocyte control of metabolic cooperativity between oocytes and companion granulosa cells: energy metabolism.">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</ref> 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.<ref name="Otsuka_2011" /> In preovulatory follicles, GDF9 promotes the production of progesterone via the stimulation of the prostaglandin- EP2 receptor signaling pathway.<ref name=" Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway."> 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</ref>
 
==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.<ref name="Otsuka_2011" /><ref name="Yan_2001">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</ref> Three particular missense mutations GDF9 <sup> P103S</sup>, GDF9 <sup> P374L </sup> and GDF9<sup> R454C </sup> have been found, although GDF9 <sup> P103S </sup> is present in women with dizygotic twins as well as women with premature ovarian failure.<ref name="Otsuka_2011" /> 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.<ref name="Otsuka_2011" /> 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.<ref name=" Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure.">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</ref><ref name=" The Bone Morphogenetic Protein System In Mammalian Reproduction.">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</ref>
 
===Link with Polycystic Ovarian Syndrome (PCOS)===
 
PCOS accounts for approximately 90% of anovulation infertility, affecting 5-10% of woman of reproductive age.<ref name=" 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.">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</ref> In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS.<ref name="Otsuka_2011" /> In particular, levels of GDF9 increase as the follicle develops from primordial stages to more mature stages.<ref name=" Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome.">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</ref> Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis.<ref name=" Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome."/> GDF9 expression is not only reduced in women with PCOS but also delayed.<ref name=" Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome."/> Despite these facts the exact link of GDF9 with PCOS is not well established.<ref name="Otsuka_2011" />
 
==Synergistic Interaction==
 
[[Bone morphogenic protein 15]] (BMP15) is highly expressed in the oocyte and the surrounding follicular cells contributing greatly to folliculogenesis and oogenesis.<ref name="Otsuka_2011" /> Like GDF9, BMP15 belongs to the TGF-ß superfamily.<ref name="Otsuka_2011" /> Differences in the synergistic action of BMP15 and GDF9 appear to be species dependent.<ref name="Otsuka_2011" /> 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.<ref name=" Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants.">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</ref> The silencing of ‘’Bmp15’’ in mice results in partial fertility but normal histological appearance of the ovary.<ref name="Yan_2001" /> 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.<ref name="Yan_2001" /> Mice with this genome also fail to release oocytes resulting in trapped oocytes in the corpus lutea.<ref name="Yan_2001" /> This phenotype is absent in ‘’Gdf9’’ silenced mice and only present a small population of ‘’Bmp15’’ silenced mice.<ref name="Yan_2001" />  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.<ref name=" 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.">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</ref>
 
GDF9 plays an important role in the development of primary [[Ovarian follicle|follicles]] in the [[ovary]].<ref>{{cite journal |vauthors=Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K |title=Physiology of GDF9 and BMP15 signalling molecules |journal=[[Anim Reprod Sci]] |volume=82-83 |issue= |pages=447–60 |year= 2004|pmid=15271472 |doi=10.1016/j.anireprosci.2004.04.021}}</ref> It has a critical role in [[granulosa cell]] and [[theca cell]] growth, as well as in differentiation and maturation of the oocyte.<ref name="Hreinsson_2002" /><ref>{{cite journal |vauthors=Su Y, Wu X, O'Brien M, Pendola F, Denegre J, Matzuk M, Eppig J |title=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 |journal=Dev Biol |volume=276 |issue=1 |pages=64–73 |year=2004 |pmid=15531364 |doi=10.1016/j.ydbio.2004.08.020}}</ref>
 
GDF9 has been connected to differences in [[ovulation]] rate<ref>{{cite journal |vauthors=McNatty K, Hudson N, Whiting L, Reader K, Lun S, Western A, Heath D, Smith P, Moore L, Juengel J |title=The Effects of Immunizing Sheep with Different BMP15 or GDF9 Peptide Sequences on Ovarian Follicular Activity and Ovulation Rate |journal=Biol Reprod |volume= 76|issue= 4|pages= 552–60|year= 2007|pmid=17093201 |doi=10.1095/biolreprod.106.054361}}</ref><ref>{{cite journal |vauthors=Juengel J, Hudson N, Whiting L, McNatty K |title=Effects of immunization against bone morphogenetic protein 15 and growth differentiation factor 9 on ovulation rate, fertilization, and pregnancy in ewes |journal=Biol Reprod |volume=70 |issue=3 |pages=557–61 |year=2004 |pmid=14585806 |doi=10.1095/biolreprod.103.023333}}</ref> and in premature cessation of ovary function,<ref>{{cite journal |vauthors=Kovanci E, Rohozinski J, Simpson J, Heard M, Bishop C, Carson S |title=Growth differentiating factor-9 mutations may be associated with premature ovarian failure |journal=Fertil Steril |volume=87 |issue=1 |pages=143–6 |year=2007 |pmid=17156781 |doi=10.1016/j.fertnstert.2006.05.079}}</ref> 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]]).<ref>{{cite journal |vauthors=Mazerbourg S, Hsueh A |title=Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands |journal=Hum Reprod Update |volume=12 |issue=4 |pages=373–83 |year= 2006|pmid=16603567 |doi=10.1093/humupd/dml014}}</ref><ref>{{cite journal |vauthors=Vitt U, Mazerbourg S, Klein C, Hsueh A |title=Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9 |journal=Biol Reprod |volume=67 |issue=2 |pages=473–80 |year=2002 |pmid=12135884 |doi=10.1095/biolreprod67.2.473}}</ref>


==References==
==References==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal  | author=McGrath SA, Esquela AF, Lee SJ |title=Oocyte-specific expression of growth/differentiation factor-9. |journal=Mol. Endocrinol. |volume=9 |issue= 1 |pages= 131-6 |year= 1995 |pmid= 7760846 |doi=  }}
*{{cite journal  |vauthors=McPherron AC, Lee SJ |title=GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. |journal=J. Biol. Chem. |volume=268 |issue= 5 |pages= 3444–9 |year= 1993 |pmid= 8429021 |doi=  }}
*{{cite journal | author=McPherron AC, Lee SJ |title=GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. |journal=J. Biol. Chem. |volume=268 |issue= 5 |pages= 3444-9 |year= 1993 |pmid= 8429021 |doi= }}
*{{cite journal   |vauthors=Dong J, Albertini DF, Nishimori K, etal |title=Growth differentiation factor-9 is required during early ovarian folliculogenesis. |journal=Nature |volume=383 |issue= 6600 |pages= 531–5 |year= 1996 |pmid= 8849725 |doi= 10.1038/383531a0 }}
*{{cite journal | author=Dong J, Albertini DF, Nishimori K, ''et al.'' |title=Growth differentiation factor-9 is required during early ovarian folliculogenesis. |journal=Nature |volume=383 |issue= 6600 |pages= 531-5 |year= 1996 |pmid= 8849725 |doi= 10.1038/383531a0 }}
*{{cite journal   |vauthors=Aaltonen J, Laitinen MP, Vuojolainen K, etal |title=Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. |journal=J. Clin. Endocrinol. Metab. |volume=84 |issue= 8 |pages= 2744–50 |year= 1999 |pmid= 10443672 |doi=10.1210/jc.84.8.2744  }}
*{{cite journal | author=Aaltonen J, Laitinen MP, Vuojolainen K, ''et al.'' |title=Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. |journal=J. Clin. Endocrinol. Metab. |volume=84 |issue= 8 |pages= 2744-50 |year= 1999 |pmid= 10443672 |doi=  }}
*{{cite journal   |vauthors=Gilboa L, Nohe A, Geissendörfer T, etal |title=Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. |journal=Mol. Biol. Cell |volume=11 |issue= 3 |pages= 1023–35 |year= 2000 |pmid= 10712517 |doi=  10.1091/mbc.11.3.1023| pmc=14828  }}
*{{cite journal  | author=Gilboa L, Nohe A, Geissendörfer T, ''et al.'' |title=Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. |journal=Mol. Biol. Cell |volume=11 |issue= 3 |pages= 1023-35 |year= 2000 |pmid= 10712517 |doi=  }}
*{{cite journal  |vauthors=Vitt UA, Mazerbourg S, Klein C, Hsueh AJ |title=Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. |journal=Biol. Reprod. |volume=67 |issue= 2 |pages= 473–80 |year= 2003 |pmid= 12135884 |doi=10.1095/biolreprod67.2.473 }}
*{{cite journal  | author=Vitt UA, Mazerbourg S, Klein C, Hsueh AJ |title=Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. |journal=Biol. Reprod. |volume=67 |issue= 2 |pages= 473-80 |year= 2003 |pmid= 12135884 |doi= }}
*{{cite journal  |vauthors=Liao WX, Moore RK, Otsuka F, Shimasaki S |title=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. |journal=J. Biol. Chem. |volume=278 |issue= 6 |pages= 3713–9 |year= 2003 |pmid= 12446716 |doi= 10.1074/jbc.M210598200 }}
*{{cite journal | author=Liao WX, Moore RK, Otsuka F, Shimasaki S |title=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. |journal=J. Biol. Chem. |volume=278 |issue= 6 |pages= 3713-9 |year= 2003 |pmid= 12446716 |doi= 10.1074/jbc.M210598200 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  |vauthors=Liao WX, Moore RK, Shimasaki S |title=Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17391–6 |year= 2004 |pmid= 14970198 |doi= 10.1074/jbc.M401050200 }}
*{{cite journal | author=Liao WX, Moore RK, Shimasaki S |title=Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17391-6 |year= 2004 |pmid= 14970198 |doi= 10.1074/jbc.M401050200 }}
*{{cite journal   |vauthors=Schmutz J, Martin J, Terry A, etal |title=The DNA sequence and comparative analysis of human chromosome 5. |journal=Nature |volume=431 |issue= 7006 |pages= 268–74 |year= 2004 |pmid= 15372022 |doi= 10.1038/nature02919 }}
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*{{cite journal   |vauthors=Dixit H, Rao LK, Padmalatha V, etal |title=Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. |journal=Menopause |volume=12 |issue= 6 |pages= 749–54 |year= 2007 |pmid= 16278619 |doi= 10.1097/01.gme.0000184424.96437.7a }}
*{{cite journal | author=Dixit H, Rao LK, Padmalatha V, ''et al.'' |title=Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. |journal=Menopause (New York, N.Y.) |volume=12 |issue= 6 |pages= 749-54 |year= 2007 |pmid= 16278619 |doi= 10.1097/01.gme.0000184424.96437.7a }}
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*{{cite journal   |vauthors=Laissue P, Christin-Maitre S, Touraine P, etal |title=Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. |journal=Eur. J. Endocrinol. |volume=154 |issue= 5 |pages= 739–44 |year= 2006 |pmid= 16645022 |doi= 10.1530/eje.1.02135 }}
*{{cite journal | author=Laissue P, Christin-Maitre S, Touraine P, ''et al.'' |title=Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. |journal=Eur. J. Endocrinol. |volume=154 |issue= 5 |pages= 739-44 |year= 2006 |pmid= 16645022 |doi= 10.1530/eje.1.02135 }}
*{{cite journal   |vauthors=Palmer JS, Zhao ZZ, Hoekstra C, etal |title=Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. |journal=J. Clin. Endocrinol. Metab. |volume=91 |issue= 11 |pages= 4713–6 |year= 2007 |pmid= 16954162 |doi= 10.1210/jc.2006-0970 }}
*{{cite journal | author=Palmer JS, Zhao ZZ, Hoekstra C, ''et al.'' |title=Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. |journal=J. Clin. Endocrinol. Metab. |volume=91 |issue= 11 |pages= 4713-6 |year= 2007 |pmid= 16954162 |doi= 10.1210/jc.2006-0970 }}
*{{cite journal   |vauthors=Chand AL, Ponnampalam AP, Harris SE, etal |title=Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. |journal=Fertil. Steril. |volume=86 |issue= 4 |pages= 1009–12 |year= 2006 |pmid= 17027369 |doi= 10.1016/j.fertnstert.2006.02.107 }}
*{{cite journal | author=Chand AL, Ponnampalam AP, Harris SE, ''et al.'' |title=Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. |journal=Fertil. Steril. |volume=86 |issue= 4 |pages= 1009-12 |year= 2006 |pmid= 17027369 |doi= 10.1016/j.fertnstert.2006.02.107 }}
*{{cite journal   |vauthors=Kovanci E, Rohozinski J, Simpson JL, etal |title=Growth differentiating factor-9 mutations may be associated with premature ovarian failure. |journal=Fertil. Steril. |volume=87 |issue= 1 |pages= 143–6 |year= 2007 |pmid= 17156781 |doi= 10.1016/j.fertnstert.2006.05.079 }}
*{{cite journal | author=Kovanci E, Rohozinski J, Simpson JL, ''et al.'' |title=Growth differentiating factor-9 mutations may be associated with premature ovarian failure. |journal=Fertil. Steril. |volume=87 |issue= 1 |pages= 143-6 |year= 2007 |pmid= 17156781 |doi= 10.1016/j.fertnstert.2006.05.079 }}
*{{cite journal   |vauthors=Hanavadi S, Martin TA, Watkins G, etal |title=The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer. |journal=Ann. Surg. Oncol. |volume=14 |issue= 7 |pages= 2159–66 |year= 2007 |pmid= 17453295 |doi= 10.1245/s10434-007-9397-5 }}
*{{cite journal | author=Hanavadi S, Martin TA, Watkins G, ''et al.'' |title=The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer. |journal=Ann. Surg. Oncol. |volume=14 |issue= 7 |pages= 2159-66 |year= 2007 |pmid= 17453295 |doi= 10.1245/s10434-007-9397-5 }}
}}
}}
{{refend}}
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==External links==
==External links==
* {{MeshName|growth+differentiation+factor+9}}
* {{MeshName|growth+differentiation+factor+9}}


{{TGF beta signaling}}
{{TGF beta signaling}}
{{TGFβ receptor superfamily modulators}}
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[[Category:Growth factors]]
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Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.[1][2]

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.[2]

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.[3] It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells.[3] Paracrine interactions between the developing oocyte and its surrounding follicular cells is essential for the correct progression of both the follicle and the oocyte.[4] GDF9 is essential for the overall process of folliculogenesis, oogenesis and ovulation and thus plays a major role in female fertility.[4]

Signaling Pathway

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).[5] Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins.[4] SMAD proteins are transcription factors found in vertebrates, insects and nematodes, and are the intercellular substrates of all TGF-ß molecules.[6] 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.[5]

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 [3] 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.[7] 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.[3] Any somatic cell formation after the primary layer is atypical and asymmetrical.[7] Normally the follicle becomes atretic and degenerates although this does not occur emphasizing the abnormality of these supporting cells.[7] GDF9 deficiency is further linked with the up regulation of inhibin.[3] 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.[8]

In vitro exposure of mammalian ovarian tissue to GDF9 promotes primary follicle progression.[9][10] GDF9 stimulates growth of preantral follicles by preventing granulosa cell apoptosis.[11] This may occur through increased follicle stimulating hormone (FSH) receptor expression or be a result of post-receptor signaling.[3]

Some sheep breeds show a range of fertility phenotypes due to eight single nucleotide polymorphisms (SNP) across the coding region of GDF9.[12] 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.[13]

Late Follicle Development

Typical of later stages of follicle development is the appearance of cumulus cells.[14] GDF9 causes the expansion of cumulus cells, a characteristic process in normal follicular development.[4] GDF9 induces hyaluronanic synthase 2 (Has2) and suppresses urokinase plasminogen activator (uPA) mRNA synthesis in granulosa cells.[14] This allows an extracellular matrix rich in hyaluronic acid, allowing the expansion of cumulus cells.[15] 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.[14][16]

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.[7] 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.[7] 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.[14] The altered phenotype observed in GDF9 deficient oocytes likely results from the lack off somatic cell input in later stages of folliculogenesis.[7]

Role in Ovulation

GDF9 is required just prior to the surge of luteinizing hormone (LH), a key event responsible for ovulation.[3] Prior to the LH surge, GDF9 supports the metabolic function of cumulus cells, allowing glycolysis and cholesterol biosynthesis.[17] 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.[3] In preovulatory follicles, GDF9 promotes the production of progesterone via the stimulation of the prostaglandin- EP2 receptor signaling pathway.[18]

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.[3][19] 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.[3] 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.[3] 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.[20][21]

Link with Polycystic Ovarian Syndrome (PCOS)

PCOS accounts for approximately 90% of anovulation infertility, affecting 5-10% of woman of reproductive age.[22] In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS.[3] In particular, levels of GDF9 increase as the follicle develops from primordial stages to more mature stages.[23] Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis.[23] GDF9 expression is not only reduced in women with PCOS but also delayed.[23] Despite these facts the exact link of GDF9 with PCOS is not well established.[3]

Synergistic Interaction

Bone morphogenic protein 15 (BMP15) is highly expressed in the oocyte and the surrounding follicular cells contributing greatly to folliculogenesis and oogenesis.[3] Like GDF9, BMP15 belongs to the TGF-ß superfamily.[3] Differences in the synergistic action of BMP15 and GDF9 appear to be species dependent.[3] 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.[24] The silencing of ‘’Bmp15’’ in mice results in partial fertility but normal histological appearance of the ovary.[19] 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.[19] Mice with this genome also fail to release oocytes resulting in trapped oocytes in the corpus lutea.[19] This phenotype is absent in ‘’Gdf9’’ silenced mice and only present a small population of ‘’Bmp15’’ silenced mice.[19] 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.[25]

GDF9 plays an important role in the development of primary follicles in the ovary.[26] It has a critical role in granulosa cell and theca cell growth, as well as in differentiation and maturation of the oocyte.[9][27]

GDF9 has been connected to differences in ovulation rate[28][29] and in premature cessation of ovary function,[30] 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).[31][32]

References

  1. ↑ 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. ↑ 2.0 2.1 "Entrez Gene: GDF9 growth differentiation factor 9".
  3. ↑ 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. ↑ 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. ↑ 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
  6. ↑ 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. ↑ 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
  8. ↑ 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. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.

Further reading

External links

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