Role of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Ovarian Function and Their Importance in Mammalian Female Fertility - A Review

  • Castro, Fernanda Cavallari de (Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo) ;
  • Cruz, Maria Helena Coelho (Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo) ;
  • Leal, Claudia Lima Verde (Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo)
  • Received : 2015.09.24
  • Accepted : 2015.12.23
  • Published : 2016.08.01


Growth factors play an important role during early ovarian development and folliculogenesis, since they regulate the migration of germ cells to the gonadal ridge. They also act on follicle recruitment, proliferation/atresia of granulosa cells and theca, steroidogenesis, oocyte maturation, ovulation and luteinization. Among the growth factors, the growth differentiation factor 9 (GDF9) and the bone morphogenetic protein 15 (BMP15), belong to the transforming growth factor beta (TGF-${\beta}$) superfamily, have been implicated as essential for follicular development. The GDF9 and BMP15 participate in the evolution of the primordial follicle to primary follicle and play an important role in the later stages of follicular development and maturation, increasing the steroidogenic acute regulatory protein expression, plasminogen activator and luteinizing hormone receptor (LHR). These factors are also involved in the interconnections between the oocyte and surrounding cumulus cells, where they regulate absorption of amino acids, glycolysis and biosynthesis of cholesterol cumulus cells. Even though the mode of action has not been fully established, in vitro observations indicate that the factors GDF9 and BMP15 stimulate the growth of ovarian follicles and proliferation of cumulus cells through the induction of mitosis in cells and granulosa and theca expression of genes linked to follicular maturation. Thus, seeking greater understanding of the action of these growth factors on the development of oocytes, the role of GDF9 and BMP15 in ovarian function is summarized in this brief review.


Supported by : FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)


  1. Aaltonen, J., M. P. Laitinen, K. Vuojolainen, R. Jaatinen, N. Horelli-Kuitunen, L. Seppa, H. Louhio, T. Tuuri, J. Sjoberg, R. Butzow, O. Hovatta, L. Dale, and O. Ritvos. 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. 84:2744-2750.
  2. Aerts, J. M. J. and P. E. J. Bols. 2010. Ovarian follicular dynamics: A review with emphasis on the bovine species. Part I: Folliculogenesis and pre-antral follicle development. Reprod. Domest. Anim. 45:171-179.
  3. Albertini, D. F., C. M. H. Combelles, E. Benecchi, and M. J. Carabatsos. 2001. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction 121:647-653.
  4. Anderson, E. and D. F. Albertini. 1976. Gap junctions between the oocyte and companion follicle cells in the mammalian ovary. J. Cell Biol. 71:680-686.
  5. Araujo, V. R., A. P. Almeida, D. M. Magalhaes, M. H. T. Matos, L. M. T. Tavares, J. R. Figueiredo, and A. P. R. Rodrigues. 2010. Role of Bone Morphogenetic Proteins-6 and -7 (BMP-6 and - 7) in the regulation of early foliculogenesis in mammals. Rev. Bras. Reproducao Anim. 34:69-78.
  6. Armstrong, D. T., P. Xia, G. Gannes, F. R. Tekpetey, and F. Khamsi. 1996. Differential effects of insulin-like growth factor-I and follicle-stimulating hormone on proliferation and differentiation of bovine cumulus cells and granulosa cells. Biol. Reprod. 54:331-338.
  7. Bodensteiner, K. J., C. M. Clay, C. L. Moeller, and H. R. Sawyer. 1999. Molecular cloning of the ovine Growth/Differentiation factor-9 gene and expression of growth/differentiation factor-9 in ovine and bovine ovaries. Biol. Reprod. 60:381-386.
  8. Buratini Jr, J. 2007. Endocrine and local control of folliculogenesis in cattle. Rev. Bras. Reproducao Anim. 31:190-196.
  9. Caixeta, E. S. 2012. Regulation of Expression of Oocyte Secreted Factors (OSFs) and Their Receptors during Bovine In vitio Maturation (IVM) and Actions in the Control of Cumulus Expansion. Ph.D. Thesis, University of Sao Paulo State, Botucatu, Sao Paulo, Brazil.
  10. Campos, C. O., A. A. Vireque, J. R. Campos, and A. C. J. S. R. Silva. 2011. The influence of interaction between oocyte and granulosa cells on the results of procedures in assisted reproduction. Femina 39:207-216.
  11. Carabatsos, M. J., J. Elvin, M. M. Matzuk, and D. F. Albertini. 1998. Characterization of oocyte and follicle development in growth differentiation factor-9-deficient mice. Dev. Biol. 204:373-384.
  12. Ceko, M. J., K. Hummitzsch, N. Hatzirodos, W. M. Bonner, J. B. Aitken, D. L. Russell, M. Lane, R. J. Rodgers, and H. H. Harris. 2015. X-Ray fluorescence imaging and other analyses identify selenium and GPX1 as important in female reproductive function. Metallomics 7:71-82.
  13. Chang, H., C. W. Brown, and M. M. Matzuk. 2002. Genetic analysis of the mammalian transforming growth factor-${\beta}$ superfamily. Endocr. Rev. 23:787-823.
  14. Derynck, R. 1998. Developmental biology: SMAD proteins and mammalian anatomy. Nature 393:737-739.
  15. Di Pasquale, E., P. Beck-Peccoz, and L. Persani. 2004. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am. J. Hum. Genet. 75:106-111.
  16. Dias, F. C. F., M. I. R. Khan, G. P. Adams, M. A. Sirard, and J. Singh. 2014. Granulosa cell function and oocyte competence: Super-follicles, super-moms and super-stimulation in cattle. Anim. Reprod. Sci. 149:80-89.
  17. Dixit, H., L. K. Rao, V. V. Padmalatha, M. Kanakavalli, M. Deenadayal, N. Gupta, B. Chakrabarty, and L. Singh. 2006. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum. Genet. 119:408-415.
  18. Dong, J., D. F. Albertini, K. Nishimori, T. R. Kumar, N. Lu, and M. M. Matzuk. 1996. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383:531-535.
  19. Dube, J. L., P. Wang, J. Elvin, K. M. Lyons, A. J. Celeste, and M. M. Matzuk. 1998. The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol. Endocrinol. (Baltimore, Md.). 12:1809-1817.
  20. Eckery, D. C., L. J. Whale, S. B. Lawrence, K. A. Wylde, K. P. McNatty, and J. L. Juengel. 2002. 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). Mol. Cell. Endocrinol. 192:115-126.
  21. Edson, M. A., A. K. Nagaraja, and M. M. Matzuk. 2009. The mammalian ovary from genesis to revelation. Endocr. Rev. 30:624-712.
  22. Elvin, J. A., C. Yan, and M. M. Matzuk. 2000. Oocyte-expressed TGF-${\beta}$ superfamily members in female fertility. Mol. Cell. Endocrinol. 159:1-5.
  23. Elvin, J. A., A. T. Clark, P. Wang, N. M. Wolfman, and M. M. Matzuk. 1999. Paracrine actions of growth differentiation factor-9 in the mammalian ovary. Mol. Endocrinol. (Baltimore, Md.). 13:1035-1048.
  24. Eppig, J. J. 2001. Oocyte control of ovarian follicular development and function in mammals. Reproduction 122:829-838.
  25. Eppig, J. J., K. Wigglesworth, and F. L. Pendola. 2002. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc. Natl. Acad. Sci. USA. 99:2890-2894.
  26. Eppig, J. J., K. Wigglesworth, F. Pendola, and Y. Hirao. 1997. Murine oocytes suppress expression of luteinizing hormone receptor messenger ribonucleic acid by granulosa cells. Biol. Reprod. 56:976-984.
  27. Eppig, J. J., M. J. O'Brien, F. L. Pendola, and S. Watanabe. 1998. Factors affecting the developmental competence of mouse oocytes grown in vitro: Follicle-stimulating hormone and insulin. Biol. Reprod. 59:1445-1453.
  28. Eppig, J. J., F. L. Pendola, K. Wigglesworth, and J. K. Pendola. 2005. Mouse oocytes regulate metabolic cooperativity between granulosa cells and oocytes: Amino acid transport. Biol. Reprod. 73:351-357.
  29. Fair, T. 2003. Follicular oocyte growth and acquisition of developmental competence. Anim. Reprod. Sci. 78:203-216.
  30. Fair, T. 2013. Molecular and endocrine determinants of oocyte competence. Anim. Reprod. 10:277-282.
  31. Franzen, P., P. ten Dijke, H. Ichijo, H. Yamashita, P. Schulz, C. H. Heldin, and K. Miyazono. 1993. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell 75:681-692.
  32. Galloway, S. M., K. P. McNatty, L. M. Cambridge, M. P. Laitinen, J. L. Juengel, T. S. Jokiranta, R. J. McLaren, K. Luiro, K. G. Dodds, G. W. Montgomery, A. E. Beattie, G. H. Davis, and O. Ritvos. 2000. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat. Genet. 25:279-283.
  33. Gandolfi, F., T. A. L. Brevini, F. Cillo, and S. Antonini. 2005. Cellular and molecular mechanisms regulating oocyte quality and the relevance for farm animal reproductive efficiency. Rev. Sci. Tech. 24:413-23.
  34. Gilchrist, R. B., L. J. Ritter, and D. T. Armstrong. 2004. Oocyte-somatic cell interactions during follicle development in mammals. Anim. Reprod. Sci. 82-83:431-446.
  35. Gilchrist, R. B., M. Lane, and J. G. Thompson. 2008. Oocyte-secreted factors: Regulators of cumulus cell function and oocyte quality. Hum. Reprod. Update 14:159-177.
  36. Gilchrist, R. B., L. J. Ritter, S. Myllymaa, N. Kaivo-Oja, R. A. Dragovic, T. E. Hickey, O. Ritvos, and D. G. Mottershead. 2006. Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation. J. Cell Sci. 119:3811-3821.
  37. Gittens, J. E. I., K. J. Barr, B. C. Vanderhyden, and G. M. Kidder. 2005. Interplay between paracrine signaling and gap junctional communication in ovarian follicles. J. Cell Sci. 118:113-122.
  38. Gottardi, F. P. and G. Z. Mingoti. 2010. Bovine oocyte maturation and influence on subsequent embryonic developmental competence. Rev. Bras. Reprod. Anim. 33:82-94.
  39. Gueripel, X., V. Brun, and A. Gougeon. 2006. 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. Biol. Reprod. 75:836-843.
  40. Gui, L.-M. and I. M. Joyce. 2005. RNA interference evidence that growth differentiation factor-9 mediates oocyte regulation of cumulus expansion in mice. Biol. Reprod. 72:195-199.
  41. Hanrahan, J. P., S. M. Gregan, P. Mulsant, M. Mullen, G. H. Davis, R. Powell, and S. M. Galloway. 2004. 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). Biol. Reprod. 70:900-909.
  42. Hatzirodos, N., H. F. Irving-Rodgers, K. Hummitzsch, M. L. Harland, S. E. Morris, and R. J. Rodgers. 2014. Transcriptome profiling of granulosa cells of bovine ovarian follicles during growth from small to large antral sizes. BMC Genomics 15:24.
  43. Hayashi, M., E. A. McGee, G. Min, C. Klein, U. M. Rose, M. Van Duin, and A. J. W. Hsueh. 1999. Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology 140:1236-1244.
  44. Heldin, C.-H., K. Miyazono, and P. ten Dijke. 1997. TGF-bold beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465-471.
  45. Hennet, M. L. and C. M. H. Combelles. 2012. The antral follicle: A microenvironment for oocyte differentiation. Int. J. Dev. Biol. 56:819-831.
  46. Hickey, T. E., D. L. Marrocco, R. B. Gilchrist, R. J. Norman, and D. T. Armstrong. 2004. Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles. Biol. Reprod. 71:45-52.
  47. Hoekstra, C., Z. Z. Zhao, C. B. Lambalk, G. Willemsen, N. G. Martin, D. I. Boomsma, and G. W. Montgomery. 2008. Dizygotic twinning. Hum. Reprod. Update 14:37-47.
  48. Huang, Q., A. P. Cheung, Y. Zhang, H.-F. Huang, N. Auersperg, and P. C. K. Leung. 2009. Effects of growth differentiation factor 9 on cell cycle regulators and ERK42/44 in human granulosa cell proliferation. Am. J. Physiol. Endocrinol. Metab. 296:E1344-E1353.
  49. Hussein, T. S., J. G. Thompson, and R. B. Gilchrist. 2006. Oocyte-secreted factors enhance oocyte developmental competence. Dev. Biol. 296:514-521.
  50. Hussein, T. S., M. L. Sutton-McDowall, R. B. Gilchrist, and J. G. Thompson. 2011. Temporal effects of exogenous oocyte-secreted factors on bovine oocyte developmental competence during IVM. Reprod. Fertil. Dev. 23:576-584.
  51. Hussein, T. S., D. A. Froiland, F. Amato, J. G. Thompson, and R. B. Gilchrist. 2005. Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins. J. Cell Sci. 118:5257-5268.
  52. Hutt, K. J. and D. F. Albertini. 2007. An oocentric view of folliculogenesis and embryogenesis. Reprod. Biomed. Online 14:758-764.
  53. Inagaki, K. and S. Shimasaki. 2010. Impaired production of BMP-15 and GDF-9 mature proteins derived from proproteins WITH mutations in the proregion. Mol. Cell. Endocrinol. 328:1-7.
  54. Jaatinen, R., M. P. Laitinen, K. Vuojolainen, J. Aaltonen, H. Louhio, K. Heikinheimo, E. Lehtonen, and O. Ritvos. 1999. Localization of growth differentiation factor-9 (GDF-9) mRNA and protein in rat ovaries and cDNA cloning of rat GDF-9 and its novel homolog GDF-9B. Mol. Cell. Endocrinol. 156:189-193.
  55. Juengel, J. L., K. J. Bodensteiner, D. A. Heath, N. L. Hudson, C. L. Moeller, P. Smith, S. M. Galloway, G. H. Davis, H. R. Sawyer, and K. P. McNatty. 2004a. Physiology of GDF9 and BMP15 signalling molecules. Anim. Reprod. Sci. 82-83:447-460.
  56. Juengel, J. L., N. L. Hudson, D. A. Heath, P. Smith, K. L. Reader, S. B. Lawrence, A. R. O'Connell, M. P. E. Laitinen, M. Cranfield, N. P. Groome, O. Ritvos, and K. P. McNatty. 2002. Growth differentiation factor 9 and bone morphogenetic protein 15 are essential for ovarian follicular development in sheep. Biol. Reprod. 67:1777-1789.
  57. Juengel, J. L. and K. P. McNatty. 2005. The role of proteins of the transforming growth factor-${\beta}$ superfamily in the intraovarian regulation of follicular development. Hum. Reprod. Update 11:144-161.
  58. Juengel, J. L., G. H. Davis, and K. P. McNatty. 2013. Using sheep lines with mutations in single genes to better understand ovarian function. Reproduction 146:R111-R123.
  59. Juengel, J. L., A. H. Bibby, K. L. Reader, S. Lun, L. D. Quirke, L. J. Haydon, and K. P. McNatty. 2004b. The role of transforming growth factor-beta (TGF-beta) during ovarian follicular development in sheep. Reprod. Biol. Endocrinol. 2:78.
  60. Laissue, P., S. Christin-Maitre, P. Touraine, F. Kuttenn, O. Ritvos, K. Aittomaki, N. Bourcigaux, L. Jacquesson, P. Bouchard, R. Frydman, D. Dewailly, A. C. Reyss, L. Jeffery, A. Bachelot, N. Massin, M. Fellous, and R. A. Veitia. 2006. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur. J. Endocrinol. 154:739-744.
  61. Laitinen, M., K. Vuojolainen, R. Jaatinen, I. Ketola, J. Aaltonen, E. Lehtonen, M. Heikinheimo, and O. Ritvos. 1998. A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis. Mech. Dev. 78:135-140.
  62. Lan, Z. J., P. Gu, X. Xu, K. J. Jackson, F. J. DeMayo, B. W. O'Malley, and A. J. Cooney. 2003. GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility. EMBO J. 22:4070-4081.
  63. Li, H.-K., T.-Y. Kuo, H.-S. Yang, L.-R. Chen, S. S.-L. Li, and H.-W. Huang. 2008a. Differential gene expression of bone morphogenetic protein 15 and growth differentiation factor 9 during in vitro maturation of porcine oocytes and early embryos. Anim. Reprod. Sci. 103:312-322.
  64. Li, Q., L. J. McKenzie, and M. M. Matzuk. 2008b. Revisiting oocyte-somatic cell interactions: In search of novel intrafollicular predictors and regulators of oocyte developmental competence. Mol. Hum. Reprod. 14:673-678.
  65. Li, Q., S. Rajanahally, M. A. Edson, and M. M. Matzuk. 2009. Stable expression and characterization of N-terminal tagged recombinant human bone morphogenetic protein 15. Mol. Hum. Reprod. 15:779-788.
  66. Lima, I. M. T., J. R. Celestino, J. R. Figueiredo, and A. P. R. Rodrigues. 2010. Role of Bone Morphogenetic Protein 15 (BMP-15) and Kit Ligand (KL) in the regulation of folliculogenesis in mammalian. Rev. Bras. Reproducao Anim. 34:3-20.
  67. Lima, R. S. 2012. The Role of Insulin-like Growth Factor-I on Germinal Vesicle Oocytes Exposed to Heat Shock. Masters Dissertation, University of Sao Paulo State, Campus of Botucatu, Sao Paulo, Brazil.
  68. Matzuk, M. M. and K. H. Burns. 2012. Genetics of mammalian reproduction: Modeling the end of the germline. Annu. Rev. Physiol. 74:503-528.
  69. Matzuk, M. M., K. H. Burns, M. M. Viveiros, and J. J. Eppig. 2002. Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science 296:2178-2180.
  70. Mazerbourg, S. and A. J. W. Hsueh. 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 12:373-383.
  71. Mazerbourg, S., C. Klein, J. Roh, N. Kaivo-Oja, D. G. Mottershead, O. Korchynskyi, O. Ritvos, and A. J. W. Hsueh. 2004. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol. Endocrinol. 18:653-665.
  72. McGrath, S. A., A. F. Esquela, and S. J. Lee. 1995. Oocyte-specific expression of growth/differentiation factor-9. Mol. Endocrinol. 9:131-136.
  73. McNatty, K. P., P. Smith, L. G. Moore, K. Reader, S. Lun, J. P. Hanrahan, N. P. Groome, M. Laitinen, O. Ritvos, and J. L. Juengel. 2005a. Oocyte-expressed genes affecting ovulation rate. Mol. Cell. Endocrinol. 234:57-66.
  74. McNatty, K. P., S. M. Galloway, T. Wilson, P. Smith, N. L. Hudson, A. O'Connell, A. H. Bibby, D. A. Heath, G. H. Davis, J. P. Hanrahan, and J. L. Juengel. 2005b. Physiological effects of major genes affecting ovulation rate in sheep. Genet. Sel. Evol. 37:S25-38.
  75. McNatty, K. P., L. G. Moore, N. L. Hudson, L. D. Quirke, S. B. Lawrence, K. Reader, J. P. Hanrahan, P. Smith, N. P. Groome, M. Laitinen, O. Ritvos, and J. L. Juengel. 2004. The oocyte and its role in regulating ovulation rate: A new paradigm in reproductive biology. Reproduction 128:379-386.
  76. McNatty, K. P., J. L. Juengel, K. L. Reader, S. Lun, S. Myllymaa, S. B. Lawrence, A. Western, M. F. Meerassahib, D. G. Mottershead, N. P. Groome, O. Ritvos, and M. P. E. Laitinen. 2005c. Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction 129:481-487.
  77. McNatty, K. P., J. L. Juengel, T. Wilson, S. M. Galloway, G. H. Davis, N. L. Hudson, C. L. Moeller, M. Cranfield, K. L. Reader, M. P. Laitinen, N. P. Groome, H. R. Sawyer, and O. Ritvos. 2003. Oocyte-derived growth factors and ovulation rate in sheep. Reprod. Suppl. 61:339-351.
  78. Mello, R. R. C., J. E. Ferreira, A. P. T. B. Silva, M. R. B. Mello, and H. B. Palhano. 2013. Initial follicular development in cattle. Rev. Bras. Reprod. Anim. 37:328-333.
  79. Miyazawa, K., M. Shinozaki, T. Hara, T. Furuya, and K. Miyazono. 2002. Two major Smad pathways in TGF-${\beta}$ superfamily signalling. Genes Cells 7:1191-1204.
  80. Moenter, S. M., R. M. Brand, A. R. Midgley, and F. J. Karsch. 1992. Dynamics of gonadotropin-releasing hormone release during a pulse. Endocrinology 130:503-510.
  81. Moore, R. K., F. Otsuka, and S. Shimasaki. 2003. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J. Biol. Chem. 278:304-310.
  82. Moore, R. K., G. F. Erickson, and S. Shimasaki. 2004. Are BMP-15 and GDF-9 primary determinants of ovulation quota in mammals? Trends Endocrinol. Metab. 15:356-361.
  83. Nishimura, R., Y. Kato, D. Chen, S. E. Harris, G. R. Mundy, and T. Yoneda. 1998. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J. Biol. Chem. 273:1872-1879.
  84. Orisaka, M., K. Tajima, B. K. Tsang, and F. Kotsuji. 2009. Oocyte-granulosa-theca cell interactions during preantral follicular development. J. Ovarian Res. 2:2-9.
  85. Orisaka, M., S. Orisaka, J.-Y. Jiang, J. Craig, Y. Wang, F. Kotsuji, and B. K. Tsang. 2006. Growth differentiation factor 9 is antiapoptotic during follicular development from preantral to early antral stage. Mol. Endocrinol. 20:2456-2468.
  86. Otsuka, F., K. J. McTavish, and S. Shimasaki. 2011. Integral role of GDF-9 and BMP-15 in ovarian function. Mol. Reprod. Dev. 78:9-21.
  87. Otsuka, F., Z. Yao, T. -H. Lee, S. Yamamoto, G. F. Erickson, and S. Shimasaki. 2000. Bone morphogenetic protein-15 identification of target cells and biological functions. J. Biol. Chem. 275:39523-39528.
  88. Palmer, J. S., Z. Z. Zhen, C. Hoekstra, N. K. Hayward, P. M. Webb, D. C. Whiteman, N. G. Martin, D. I. Boomsma, D. L. Duffy, and G. W. Montgomery. 2006. Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. J. Clin. Endocrinol. Metab. 91:4713-4716.
  89. Pangas, S. A. and M. M. Matzuk. 2005. The art and artifact of GDF9 activity: Cumulus expansion and the cumulus expansion-enabling factor. Biol. Reprod. 73:582-585.
  90. Pangas, S. A., C. J. Jorgez, and M. M. Matzuk. 2004. Growth differentiation factor 9 regulates expression of the bone morphogenetic protein antagonist gremlin. J. Biol. Chem. 279:32281-32286.
  91. Paulini, F. 2010. Expression of Growth and Differentiation Factor 9 (GDF9) and Bone Morphogenetic Protein 15(BMP15) and Their Effect on In vitro Luteinization of Bovine Granulosa Cells. Masters Dissertation, School of Agronomy and Veterinary Medicine - UnB, Brasilia, DF, Brazil.
  92. Peng, J., Q. Li, K. Wigglesworth, A. Rangarajan, C. Kattamuri, R. T. Peterson, J. J. Eppig, T. B. Thompson, and M. M. Matzuk. 2013. Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions. Proc. Natl. Acad. Sci. USA. 110:E776-785.
  93. Reader, K. L., D. A. Heath, S. Lun, C. J. McIntosh, A. H. Western, R. P. Littlejohn, K. P. McNatty, and J. L. Juengel. 2011. Signalling pathways involved in the cooperative effects of ovine and murine GDF9+BMP15-stimulated thymidine uptake by rat granulosa cells. Reproduction 142:123-131.
  94. Richard, F. J. and M. A. Sirard. 1996. Effects of follicular cells on oocyte maturation. I: Effects of follicular hemisections on bovine oocyte maturation in vitro. Biol. Reprod. 54:16-21.
  95. Sanchez, F. and J. Smitz. 2012. Molecular control of oogenesis. Biochim. Biophys. Acta. 1822:1896-1912.
  96. Shimasaki, S., R. K. Moore, G. F. Erickson, and F. Otsuka. 2003. The role of bone morphogenetic proteins in ovarian function. Reprod. Suppl. 61:323-337.
  97. Shimasaki, S., R. K. Moore, F. Otsuka, and G. F. Erickson. 2004. The bone morphogenetic protein system in mammalian reproduction. Endocr. Rev. 25:72-101.
  98. Silva, J. R. V., R. Van Den Hurk, H. T. A. Van Tol, B. A. J. Roelen, and J. R. Figueiredo. 2005. Expression of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), and BMP receptors in the ovaries of goats. Mol. Reprod. Dev. 70:11-19.
  99. Silva, J. R. V., R. Van Den Hurk, M. H. T. Matos, R. R. Santos, C. Pessoa, M. O. Moraes, and J. R. Figueiredo. 2004. Influences of FSH and EGF on primordial follicles during in vitro culture of caprine ovarian cortical tissue. Theriogenology 61:1691-1704.
  100. Silva, J. R. V., C. C. F. Leitao, and I. R. Brito. 2009. Transforming growth factors -${\beta}$ superfamily members and control of folliculogenesis in mammals. Rev. Bras. Reprod. Anim. 33:149-160.
  101. Silva, J. R. V., M. A. L. Ferreira, S. H. F. Costa, and J. R. Figuereiredo. 2002. Morphological features and control of follicular growth during folliculogenesis in domestic ruminants. Ciencia Anim. 12:105-117.
  102. Spicer, L. J., P. Y. Aad, D. Allen, S. Mazerbourg, and A. J. Hsueh. 2006. Growth differentiation factor-9 has divergent effects on proliferation and steroidogenesis of bovine granulosa cells. J. Endocrinol. 189:329-339.
  103. Su, Y. Q., X. Wu, M. J. O'Brien, F. L. Pendola, J. N. Denegre, M. M. Matzuk, and J. J. Eppig. 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. 276:64-73.
  104. Su, Y.-Q., K. Sugiura, and J. Eppig. 2009. Mouse oocyte control of granulosa cell development and function: Paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27:32-42.
  105. Su, Y.-Q., K. Sugiura, K. Wigglesworth, M. J. O'Brien, J. P. Affourtit, S. Pangas, M. M. Matzuk, and J. J. Eppig. 2008. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development 135:111-121.
  106. Sutton, M. L., R. B. Gilchrist, and J. G. Thompson. 2003. Effect of in-vivo and in-vitro environments on the metabolism of the cumulus-oocyte complex and its influence on oocyte developmental capacity. Hum. Reprod. Update 9:35-48.
  107. Tanghe, S., A. Van Soom, H. Nauwynck, M. Coryn, and A. De Kruif. 2002. Minireview: Functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization. Mol. Mol. Reprod. Dev. 61:414-424.
  108. Vanderhyden, B. C. 1996. Oocyte-secreted factros regulate granulosa cell steroidogenesis. Zygote 4:317-321.
  109. Vanderhyden, B. C. and A. M. Tonary. 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.
  110. Vanderhyden, B. C., E. A. Macdonald, E. Nagyova, and A. Dhawan. 2003. Evaluation of members of the TGFbeta superfamily as candidates for the oocyte factors that control mouse cumulus expansion and steroidogenesis. Reprod. Suppl. 61:55-70.
  111. Vitt, U. A. and A. J. Hsueh. 2001. Stage-dependent role of growth differentiation factor-9 in ovarian follicle development. Mol. Cell Endocrinol. 183:171-177.
  112. Vitt, U. A., M. Hayashi, C. Klein, and A. J. Hsueh. 2000a. 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.
  113. Vitt, U. A., E. A. McGee, M. Hayashi, and A. J. W. Hsueh. 2000b. 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.
  114. Vitt, U. A., S. Mazerbourg, C. Klein, and A. J. W. Hsueh. 2002. Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol. Reprod. 67:473-480.
  115. Webb, R., B. Nicholas, J. G. Gong, B. K. Campbell, C. G. Gutierrez, H. A. Garverick, and D. G. Armstrong. 2003. Mechanisms regulating follicular development and selection of the dominant follicle. Reprod. Suppl. 61:71-90.
  116. Wigglesworth, K., K.-B. Lee, M. J. O'Brien, J. Peng, M. M. Matzuk, and J. J. Eppig. 2013. Bidirectional communication between oocytes and ovarian follicular somatic cells is required for meiotic arrest of mammalian oocytes. Proc. Natl. Acad. Sci. USA. 110:E3723-E3729.
  117. Yan, C., P. Wang, J. DeMayo, F. J. DeMayo, J. A. Elvin, C. Carino, S. V Prasad, S. S. Skinner, B. S. Dunbar, J. L. Dube, A. J. Celeste, and M. M. Matzuk. 2001. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol. Endocrinol. 15:854-866.
  118. Yeo, C. X., R. B. Gilchrist, J. G. Thompson, and M. Lane. 2008. Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice. Hum. Reprod. 23:67-73.
  119. Ying, Y., X. M. Liu, A. Marble, K. A. Lawson, and G. Q. Zhao. 2000. Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol. Endocrinol. 14:1053-1063.
  120. Yoshino, O., H. E. McMahon, S. Sharma, and S. Shimasaki. 2006. A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse. Proc. Natl. Acad. Sci. USA. 103:10678-10683.
  121. Young, J. M. and A. S. McNeilly. 2010. Theca: The forgotten cell of the ovarian follicle. Reproduction 140:489-504.
  122. Zhao, H., Y. Qin, E. Kovanci, J. L. Simpson, Z.-J. Chen, and A. Rajkovic. 2007. Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertil. Steril. 88:1474-1476.

Cited by

  1. Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells vol.2017, pp.1687-9678, 2017,
  2. Genetic polymorphism of growth differentiation factor 9 (GDF9) gene related to fecundity in two Egyptian sheep breeds vol.34, pp.12, 2017,
  3. splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy vol.38, pp.8, 2017,
  4. Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity vol.6, pp.2046-1402, 2017,
  5. Paracrine effects of human amniotic epithelial cells protect against chemotherapy-induced ovarian damage vol.8, pp.1, 2017,
  6. Maximum-likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility pp.20457758, 2017,
  7. culture had no adverse effect on the follicular development and gene expression of stimulated human ovarian tissue vol.44, pp.3, 2018,
  8. Effect of platelet-rich plasma (PRP) on ovarian structures in cyclophosphamide-induced ovarian failure in female rats: a stereological study vol.28, pp.9, 2018,
  9. GDF-9 and BMP-15 direct the follicle symphony vol.35, pp.10, 2018,
  10. Molecular Mechanisms of Prophase I Meiotic Arrest Maintenance and Meiotic Resumption in Mammalian Oocytes pp.1933-7205, 2018,