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Gene Review

GDF9  -  growth differentiation factor 9

Homo sapiens

Synonyms: GDF-9, Growth/differentiation factor 9
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Disease relevance of GDF9

  • Based on these findings we propose a novel hypothesis that a decrease in GDF-9 secretion may be involved in causing infertility in homozygous Inverdale ewes [1].

High impact information on GDF9

  • GDF-9 messenger RNA is synthesized only in the oocyte from the primary one-layer follicle stage until after ovulation [2].
  • Here we analyse ovaries from GDF-9-deficient female mice and demonstrate that primordial and primary one-layer follicles can be formed, but there is a block in follicular development beyond the primary one-layer follicle stage which leads to complete infertility [2].
  • These data indicate that CPEB controls the expression of Gdf9 mRNA, which in turn is necessary for oocyte-follicle development [3].
  • In chromatin immunoprecipitation assays, DNA sequences from Pou5f1 and Gdf9 promoters co-precipitated with anti-NOBOX antibody [4].
  • Bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9) are members of the transforming growth factor-beta superfamily [1].

Biological context of GDF9

  • Consistent with these findings, oocytes, GDF9 and TGFbeta1 all activated SMAD2/3 reporter constructs in transfected GC, and led to phosphorylation of SMAD2 proteins in treated cells [5].
  • Although spontaneous in vitro oocyte maturation occurred normally, oocyte fertilization and preimplantation embryogenesis were significantly altered in the DM, suggesting that the full complement of both GDF9 and BMP15 are essential for the development and function of oocytes [6].
  • Because searches of the human genome for genes with sequence homology to known serine/threonine kinase receptors failed to reveal uncharacterized receptor genes, GDF9 likely interacts with the known type II and type I activin receptor-like kinase (ALK) receptors in granulosa cells [7].
  • GDF-9 expression is essential for early follicle development, and the presence of the type II and type I receptors in the neonatal rat ovary was verified by reverse transcription polymerase chain reaction [8].
  • Short-term (that is, primary and booster) immunisation with a GDF9 or BMP15 peptide-protein conjugate has been shown to enhance ovulation rate and lamb production [9].

Anatomical context of GDF9

  • An activin receptor-like kinase (ALK) 4/5/7 inhibitor, SB431542, also antagonised both oocyte and GDF9 bioactivity in a dose-dependent manner [5].
  • The roles of BMPRII and ALK5 as receptors for GDF9 were validated in granulosa cells using gene "knock-down" approaches [7].
  • Likewise, in a GDF9-non-responsive cell line, overexpression of ALK5, but none of the other six type I receptors, conferred GDF9 responsiveness [7].
  • Thus, since the mRNAs encoding GDF9 and BMP15 were not observed until follicular formation, it is unlikely that these proteins have any role in early germ cell development [10].
  • Both GDF9 and BMP15 proteins are present in follicular fluid, indicating that they are secreted products [9].

Associations of GDF9 with chemical compounds


Other interactions of GDF9


Analytical, diagnostic and therapeutic context of GDF9

  • Based on phylogenetic and sequence analyses, we predicted that GDF-9 likely interacts with known type I and type II receptors [8].
  • We determined here by in situ hybridization and immunohistochemical analyses the localization of the GDF-9 messenger ribonucleic acid (mRNA) and protein during human folliculogenesis [16].
  • The GDF-9 transcripts were not detected in primordial follicles, but they are abundantly expressed in primary follicles in frozen sections of ovarian cortical tissue material obtained at laparoscopic surgery [16].
  • One mother of DZ twins was selected from 279 of the 915 families, and a DNA sample was screened for rare variants in GDF9 using denaturant HPLC [17].
  • RESULTS: This case-control study revealed eight mutations in the GDF9 gene, including five novel mutations: c.1-8C>T, c.199A>C (p.Lys67Glu), c. 205C>T, c.646G>A (p.Val216Mat), and c.1353C>T, and three documented mutations: c.398-39C>G, c.447C>T, and c.546G>A [18].


  1. 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. Liao, W.X., Moore, R.K., Otsuka, F., Shimasaki, S. J. Biol. Chem. (2003) [Pubmed]
  2. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Dong, J., Albertini, D.F., Nishimori, K., Kumar, T.R., Lu, N., Matzuk, M.M. Nature (1996) [Pubmed]
  3. CPEB controls oocyte growth and follicle development in the mouse. Racki, W.J., Richter, J.D. Development (2006) [Pubmed]
  4. Characterization of NOBOX DNA Binding Specificity and Its Regulation of Gdf9 and Pou5f1 Promoters. Choi, Y., Rajkovic, A. J. Biol. Chem. (2006) [Pubmed]
  5. Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation. Gilchrist, R.B., Ritter, L.J., Myllymaa, S., Kaivo-Oja, N., Dragovic, R.A., Hickey, T.E., Ritvos, O., Mottershead, D.G. J. Cell. Sci. (2006) [Pubmed]
  6. 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. Su, Y.Q., Wu, X., O'Brien, M.J., Pendola, F.L., Denegre, J.N., Matzuk, M.M., Eppig, J.J. Dev. Biol. (2004) [Pubmed]
  7. Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands. Mazerbourg, S., Hsueh, A.J. Hum. Reprod. Update (2006) [Pubmed]
  8. Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Vitt, U.A., Mazerbourg, S., Klein, C., Hsueh, A.J. Biol. Reprod. (2002) [Pubmed]
  9. The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. McNatty, K.P., Moore, L.G., Hudson, N.L., Quirke, L.D., Lawrence, S.B., Reader, K., Hanrahan, J.P., Smith, P., Groome, N.P., Laitinen, M., Ritvos, O., Juengel, J.L. Reproduction (2004) [Pubmed]
  10. Expression of mRNA encoding growth differentiation factor 9 and bone morphogenetic protein 15 during follicular formation and growth in a marsupial, the brushtail possum (Trichosurus vulpecula). Eckery, D.C., Whale, L.J., Lawrence, S.B., Wylde, K.A., McNatty, K.P., Juengel, J.L. Mol. Cell. Endocrinol. (2002) [Pubmed]
  11. Local roles of TGF-beta superfamily members in the control of ovarian follicle development. Knight, P.G., Glister, C. Anim. Reprod. Sci. (2003) [Pubmed]
  12. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. 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. Mol. Endocrinol. (2001) [Pubmed]
  13. Oocyte Bone Morphogenetic Protein 15, but not Growth Differentiation Factor 9, Is Increased During Gonadotropin-Induced Follicular Development in the Immature Mouse and Is Associated with Cumulus Oophorus Expansion. Gu??ripel, X., Brun, V., Gougeon, A. Biol. Reprod. (2006) [Pubmed]
  14. Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer. Hall, V.J., Compton, D., Stojkovic, P., Nesbitt, M., Herbert, M., Murdoch, A., Stojkovic, M. Hum. Reprod. (2007) [Pubmed]
  15. Oocyte-secreted factors enhance oocyte developmental competence. Hussein, T.S., Thompson, J.G., Gilchrist, R.B. Dev. Biol. (2006) [Pubmed]
  16. Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. Aaltonen, J., Laitinen, M.P., Vuojolainen, K., Jaatinen, R., Horelli-Kuitunen, N., Seppä, L., Louhio, H., Tuuri, T., Sjöberg, J., Bützow, R., Hovata, O., Dale, L., Ritvos, O. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  17. Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. Palmer, J.S., Zhao, Z.Z., Hoekstra, C., Hayward, N.K., Webb, P.M., Whiteman, D.C., Martin, N.G., Boomsma, D.I., Duffy, D.L., Montgomery, G.W. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  18. Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Dixit, H., Rao, L.K., Padmalatha, V., Kanakavalli, M., Deenadayal, M., Gupta, N., Chakravarty, B., Singh, L. Menopause (New York, N.Y.) (2005) [Pubmed]
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