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GDF-9 and BMP-15 direct the follicle symphony

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Abstract

Understanding the physiology underlying the complex dialog between the oocyte and its surrounding somatic cells within the ovarian follicle has been crucial in defining optimal procedures for the development of clinical approaches in ART for women suffering from infertility and ovarian dysfunction. Recent studies have implicated oocyte-secreted factors like growth differentiation factor 9 (GDF-9) and bone morphogenetic protein 15 (BMP-15), members of the transforming growth factor-beta (TGFβ) superfamily, as potent regulators of folliculogenesis and ovulation. These two factors act as biologically active heterodimers or as homodimers in a synergistic cooperation. Through autocrine and paracrine mechanisms, the GDF-9 and BMP-15 system has been shown to regulate growth, differentiation, and function of granulosa and thecal cells during follicular development playing a vital role in oocyte development, ovulation, fertilization, and embryonic competence. The present mini-review provides an overview of recent findings relating GDF-9 and BMP-15 as fundamental factors implicated in the regulation of ovarian function and discusses their potential role as markers of oocyte quality in women.

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References

  1. Richards JS, Fitzpatrick SL, Clemens JW, Morris JK, Alliston T, Sirois J. Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes. Recent Prog Horm Res. 1995;50:223–54.

    CAS  PubMed  Google Scholar 

  2. McGinnis LK, Limback SD, Albertini DF. Signaling modalities during oogenesis in mammals. Curr Top Dev Biol. 2013;102:227–42.

    Article  CAS  PubMed  Google Scholar 

  3. Albertini DF, Barrett SL. Oocyte-somatic cell communication. Reprod Suppl. 2003;61:49–54.

    CAS  PubMed  Google Scholar 

  4. Rodrigues P, Limback D, McGinnis LK, Plancha CE, Albertini DF. Oogenesis: prospects and challenges for the future. J Cell Physiol. 2008;216(2):355–65.

    Article  CAS  PubMed  Google Scholar 

  5. Carabatsos MJ, Sellitto C, Goodenough DA, Albertini DF. Oocyte-granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence. Dev Biol. 2000;226(2):167–79.

    Article  CAS  PubMed  Google Scholar 

  6. Gilchrist RB, Ritter LJ, Armstrong DT. Oocyte-somatic cell interactions during follicle development in mammals. Anim Reprod Sci. 2004;82-83:431–46.

    Article  CAS  PubMed  Google Scholar 

  7. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17(2):121–55.

    Article  CAS  PubMed  Google Scholar 

  8. Albertini DF. The Mammalian Oocyte. In: The Mammalian Oocyte, in Knobil and Neill's Physiology of Reproduction (Fourth Edition). Editor: A.Z. Tony Plant; 2015. p. 59–97.

    Chapter  Google Scholar 

  9. Monniaux D. Driving folliculogenesis by the oocyte-somatic cell dialog: lessons from genetic models. Theriogenology. 2016;86(1):41–53.

    Article  CAS  PubMed  Google Scholar 

  10. Falck B. Site of production of oestrogen in rat ovary as studied in micro-transplants. Acta Physiol Scand Suppl. 1959;47(163):1–101.

    CAS  PubMed  Google Scholar 

  11. el-Fouly MA, et al. Role of the ovum in follicular luteinization. Endocrinology. 1970;87(2):286–93.

    Article  CAS  PubMed  Google Scholar 

  12. Nekola MV, Nalbandov AV. Morphological changes of rat follicular cells as influenced by oocytes. Biol Reprod. 1971;4(2):154–60.

    Article  CAS  PubMed  Google Scholar 

  13. Hutt KJ, Albertini DF. An oocentric view of folliculogenesis and embryogenesis. Reprod BioMed Online. 2007;14(6):758–64.

    Article  CAS  PubMed  Google Scholar 

  14. Erickson GF, Shimasaki S. The role of the oocyte in folliculogenesis. Trends Endocrinol Metab. 2000;11(5):193–8.

    Article  CAS  PubMed  Google Scholar 

  15. Matzuk MM, Burns KH, Viveiros MM, Eppig JJ. Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science. 2002;296(5576):2178–80.

    Article  CAS  PubMed  Google Scholar 

  16. Gilchrist RB, Lane M, Thompson JG. Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum Reprod Update. 2008;14(2):159–77.

    Article  CAS  PubMed  Google Scholar 

  17. Eppig JJ. Oocyte control of ovarian follicular development and function in mammals. Reproduction. 2001;122(6):829–38.

    Article  CAS  PubMed  Google Scholar 

  18. Eppig JJ, Chesnel F, Hirao Y, O'Brien MJ, Pendola FL, Watanabe S, et al. Oocyte control of granulosa cell development: how and why. Hum Reprod. 1997;12(11 Suppl):127–32.

    CAS  PubMed  Google Scholar 

  19. Hussein TS, Thompson JG, Gilchrist RB. Oocyte-secreted factors enhance oocyte developmental competence. Dev Biol. 2006;296(2):514–21.

    Article  CAS  PubMed  Google Scholar 

  20. Su YQ, Sugiura K, Eppig JJ. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin Reprod Med. 2009;27(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vanderhyden BC, et al. Evaluation of members of the TGFbeta superfamily as candidates for the oocyte factors that control mouse cumulus expansion and steroidogenesis. Reprod Suppl. 2003;61:55–70.

    CAS  PubMed  Google Scholar 

  22. Vanderhyden BC, Tonary AM. Differential regulation of progesterone and estradiol production by mouse cumulus and mural granulosa cells by A factor(s) secreted by the oocyte. Biol Reprod. 1995;53(6):1243–50.

    Article  CAS  PubMed  Google Scholar 

  23. Eppig JJ, Wigglesworth K, Pendola F, Hirao Y. Murine oocytes suppress expression of luteinizing hormone receptor messenger ribonucleic acid by granulosa cells. Biol Reprod. 1997;56(4):976–84.

    Article  CAS  PubMed  Google Scholar 

  24. Gilchrist RB, et al. Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation. J Cell Sci. 2006;119(Pt 18):3811–21.

    Article  CAS  PubMed  Google Scholar 

  25. Eppig JJ, Pendola FL, Wigglesworth K. Mouse oocytes suppress cAMP-induced expression of LH receptor mRNA by granulosa cells in vitro. Mol Reprod Dev. 1998;49(3):327–32.

    Article  CAS  PubMed  Google Scholar 

  26. Gilchrist RB, Ritter LJ, Armstrong DT. Mouse oocyte mitogenic activity is developmentally coordinated throughout folliculogenesis and meiotic maturation. Dev Biol. 2001;240(1):289–98.

    Article  CAS  PubMed  Google Scholar 

  27. Armstrong DT, Xia P, de Gannes G, Tekpetey FR, Khamsi F. 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. 1996;54(2):331–8.

    Article  CAS  PubMed  Google Scholar 

  28. Li R, Norman RJ, Armstrong DT, Gilchrist RB. Oocyte-secreted factor(s) determine functional differences between bovine mural granulosa cells and cumulus cells. Biol Reprod. 2000;63(3):839–45.

    Article  CAS  PubMed  Google Scholar 

  29. Coskun S, Uzumcu M, Lin YC, Friedman CI, Alak BM. Regulation of cumulus cell steroidogenesis by the porcine oocyte and preliminary characterization of oocyte-produced factor(s). Biol Reprod. 1995;53(3):670–5.

    Article  CAS  PubMed  Google Scholar 

  30. Hussein TS, et al. Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins. J Cell Sci. 2005;118(Pt 22):5257–68.

    Article  CAS  PubMed  Google Scholar 

  31. Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191–206.

    Article  CAS  PubMed  Google Scholar 

  32. Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev. 2002;23(6):787–823.

    Article  CAS  PubMed  Google Scholar 

  33. Juengel JL, McNatty KP. The role of proteins of the transforming growth factor-beta superfamily in the intraovarian regulation of follicular development. Hum Reprod Update. 2005;11(2):143–60.

    Article  CAS  PubMed  Google Scholar 

  34. Chang HM, Qiao J, Leung PC. Oocyte-somatic cell interactions in the human ovary-novel role of bone morphogenetic proteins and growth differentiation factors. Hum Reprod Update. 2016;23(1):1–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. de Castro FC, Cruz MH, Leal CL. 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. 2016;29(8):1065–74.

    Article  PubMed  CAS  Google Scholar 

  36. Persani L, Rossetti R, di Pasquale E, Cacciatore C, Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Hum Reprod Update. 2014;20(6):869–83.

    Article  CAS  PubMed  Google Scholar 

  37. Otsuka F, McTavish KJ, Shimasaki S. Integral role of GDF-9 and BMP-15 in ovarian function. Mol Reprod Dev. 2011;78(1):9–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shimasaki S, Zachow RJ, Li D, Kim H, Iemura SI, Ueno N, et al. A functional bone morphogenetic protein system in the ovary. Proc Natl Acad Sci U S A. 1999;96(13):7282–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berisha B, Schams D, Kosmann M, Amselgruber W, Einspanier R. Expression and localisation of vascular endothelial growth factor and basic fibroblast growth factor during the final growth of bovine ovarian follicles. J Endocrinol. 2000;167(3):371–82.

    Article  CAS  PubMed  Google Scholar 

  40. Shimasaki S, Moore RK, Otsuka F, Erickson GF. The bone morphogenetic protein system in mammalian reproduction. Endocr Rev. 2004;25(1):72–101.

    Article  CAS  PubMed  Google Scholar 

  41. McPherron AC, Lee SJ. GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. J Biol Chem. 1993;268(5):3444–9.

    CAS  PubMed  Google Scholar 

  42. McGrath SA, Esquela AF, Lee SJ. Oocyte-specific expression of growth/differentiation factor-9. Mol Endocrinol. 1995;9(1):131–6.

    CAS  PubMed  Google Scholar 

  43. Laitinen M, Vuojolainen K, Jaatinen R, Ketola I, Aaltonen J, Lehtonen E, et al. A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis. Mech Dev. 1998;78(1–2):135–40.

    Article  CAS  PubMed  Google Scholar 

  44. Dube JL, Wang P, Elvin J, Lyons KM, Celeste AJ, Matzuk MM. The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol Endocrinol. 1998;12(12):1809–17.

    Article  CAS  PubMed  Google Scholar 

  45. Incerti B, Dong J, Borsani G, Matzuk MM. Structure of the mouse growth/differentiation factor 9 gene. Biochim Biophys Acta. 1994;1222(1):125–8.

    Article  CAS  PubMed  Google Scholar 

  46. Ahmad HI, et al. Maximum-likelihood approaches reveal signatures of positive selection in BMP-15 and GDF-9 genes modulating ovarian function in mammalian female fertility, in Ecol Evol. 2017. p. 8895–902.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ahmad HI, Ahmad MJ, Adeel MM, Asif AR, du X. Positive selection drives the evolution of endocrine regulatory bone morphogenetic protein system in mammals. Oncotarget. 2018;9(26):18435–45.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mottershead DG, Pulkki MM, Muggalla P, Pasternack A, Tolonen M, Myllymaa S, et al. Characterization of recombinant human growth differentiation factor-9 signaling in ovarian granulosa cells. Mol Cell Endocrinol. 2008;283(1–2):58–67.

    Article  CAS  PubMed  Google Scholar 

  49. Paulini F, Melo EO. The role of oocyte-secreted factors GDF-9 and BMP-15 in follicular development and oogenesis. Reprod Domest Anim. 2011;46(2):354–61.

    Article  CAS  PubMed  Google Scholar 

  50. McIntosh CJ, Lun S, Lawrence S, Western AH, McNatty KP, Juengel JL. The proregion of mouse BMP-15 regulates the cooperative interactions of BMP-15 and GDF-9. Biol Reprod. 2008;79(5):889–96.

    Article  CAS  PubMed  Google Scholar 

  51. Yan C, Wang P, DeMayo J, DeMayo FJ, Elvin JA, Carino C, et al. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol. 2001;15(6):854–66.

    Article  CAS  PubMed  Google Scholar 

  52. Peng J, Li Q, Wigglesworth K, Rangarajan A, Kattamuri C, Peterson RT, et al. Growth differentiation factor 9: bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions. Proc Natl Acad Sci U S A. 2013;110(8):E776–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mottershead DG, Sugimura S, al-Musawi SL, Li JJ, Richani D, White MA, et al. Cumulin, an oocyte-secreted heterodimer of the transforming growth factor-beta family, is a potent activator of granulosa cells and improves oocyte quality. J Biol Chem. 2015;290(39):24007–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Su YQ, Sugiura K, Wigglesworth K, O'Brien MJ, Affourtit JP, Pangas SA, et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP-15 and GDF-9 control cholesterol biosynthesis in cumulus cells. Development. 2008;135(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  55. Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, et al. Oocyte-derived BMP-15 and FGFs cooperate to promote glycolysis in cumulus cells. Development. 2007;134(14):2593–603.

    Article  CAS  PubMed  Google Scholar 

  56. Diaz FJ, Wigglesworth K, Eppig JJ. Oocytes are required for the preantral granulosa cell to cumulus cell transition in mice. Dev Biol. 2007;305(1):300–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hashimoto O, Moore RK, Shimasaki S. Posttranslational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota. Proc Natl Acad Sci U S A. 2005;102(15):5426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pangas SA, Matzuk MM. The art and artifact of GDF-9 activity: cumulus expansion and the cumulus expansion-enabling factor. Biol Reprod. 2005;73(4):582–5.

    Article  CAS  PubMed  Google Scholar 

  59. Diaz FJ, Wigglesworth K, Eppig JJ. Oocytes determine cumulus cell lineage in mouse ovarian follicles. J Cell Sci. 2007;120(Pt 8):1330–40.

    Article  CAS  PubMed  Google Scholar 

  60. Ernst EH, Franks S, Hardy K, Villesen P, Lykke-Hartmann K. Granulosa cells from human primordial and primary follicles show differential global gene expression profiles. Hum Reprod. 2018;33(4):666–79.

    Article  CAS  PubMed  Google Scholar 

  61. Chang HM, Cheng JC, Leung PC. Theca-derived BMP4 and BMP7 down-regulate connexin43 expression and decrease gap junction intercellular communication activity in immortalized human granulosa cells. J Clin Endocrinol Metab. 2013;98(3):E437–45.

    Article  CAS  PubMed  Google Scholar 

  62. Chang HM, Cheng JC, Taylor E, Leung PCK. Oocyte-derived BMP-15 but not GDF-9 down-regulates connexin43 expression and decreases gap junction intercellular communication activity in immortalized human granulosa cells. Mol Hum Reprod. 2014;20(5):373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature. 1996;383(6600):531–5.

    Article  CAS  PubMed  Google Scholar 

  64. Galloway SM, McNatty KP, Cambridge LM, Laitinen MPE, Juengel JL, Jokiranta TS, et al. Mutations in an oocyte-derived growth factor gene (BMP-15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet. 2000;25(3):279–83.

    Article  CAS  PubMed  Google Scholar 

  65. Gueripel X, Brun V, Gougeon A. 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. 2006;75(6):836–43.

    Article  CAS  PubMed  Google Scholar 

  66. Elvin JA, Yan C, Wang P, Nishimori K, Matzuk MM. Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. Mol Endocrinol. 1999;13(6):1018–34.

    Article  CAS  PubMed  Google Scholar 

  67. Li JJ, et al. Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes, in Mol Endocrinol. 2015. p. 40–52.

    Article  PubMed  CAS  Google Scholar 

  68. Hennet ML, Combelles CM. The antral follicle: a microenvironment for oocyte differentiation. Int J Dev Biol. 2012;56(10–12):819–31.

    Article  CAS  PubMed  Google Scholar 

  69. de Caestecker M. The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev. 2004;15(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  70. Moore RK, Otsuka F, Shimasaki S. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J Biol Chem. 2003;278(1):304–10.

    Article  CAS  PubMed  Google Scholar 

  71. Mazerbourg S, Klein C, Roh J, Kaivo-Oja N, Mottershead DG, Korchynskyi O, et al. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol Endocrinol. 2004;18(3):653–65.

    Article  CAS  PubMed  Google Scholar 

  72. Vitt UA, Mazerbourg S, Klein C, Hsueh AJW. Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol Reprod. 2002;67(2):473–80.

    Article  CAS  PubMed  Google Scholar 

  73. Mazerbourg S, Hsueh AJ. 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. 2006;12(4):373–83.

    Article  CAS  PubMed  Google Scholar 

  74. Franzen P, et al. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell. 1993;75(4):681–92.

    Article  CAS  PubMed  Google Scholar 

  75. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390(6659):465–71.

    Article  CAS  PubMed  Google Scholar 

  76. Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells. 2002;7(12):1191–204.

    Article  CAS  PubMed  Google Scholar 

  77. Reader KL, Heath DA, Lun S, McIntosh CJ, Western AH, Littlejohn RP, et al. Signalling pathways involved in the cooperative effects of ovine and murine GDF-9+BMP-15-stimulated thymidine uptake by rat granulosa cells. Reproduction. 2011;142(1):123–31.

    Article  CAS  PubMed  Google Scholar 

  78. Mottershead DG, Ritter LJ, Gilchrist RB. Signalling pathways mediating specific synergistic interactions between GDF-9 and BMP-15. Mol Hum Reprod. 2012;18(3):121–8.

    Article  CAS  PubMed  Google Scholar 

  79. Reader KL, Mottershead DG, Martin GA, Gilchrist RB, Heath DA, McNatty KP, et al. Signalling pathways involved in the synergistic effects of human growth differentiation factor 9 and bone morphogenetic protein 15. Reprod Fertil Dev. 2016;28(4):491–8.

    Article  CAS  PubMed  Google Scholar 

  80. Chen H, Liu C, Jiang H, Gao Y, Xu M, Wang J, et al. Regulatory role of miRNA-375 in expression of BMP-15/GDF-9 receptors and its effect on proliferation and apoptosis of bovine cumulus cells. Cell Physiol Biochem. 2017;41(2):439–50.

    Article  CAS  PubMed  Google Scholar 

  81. Liu C, Yuan B, Chen H, Xu M, Sun X, Xu JJ, et al. Effects of MiR-375-BMPR2 as a key factor downstream of BMP-15/GDF-9 on the Smad1/5/8 and Smad2/3 signaling pathways. Cell Physiol Biochem. 2018;46(1):213–25.

    Article  CAS  PubMed  Google Scholar 

  82. Gilchrist RB, Ritter LJ. Differences in the participation of TGFB superfamily signalling pathways mediating porcine and murine cumulus cell expansion. Reproduction. 2011;142(5):647–57.

    Article  CAS  PubMed  Google Scholar 

  83. Chang HM, Cheng JC, Klausen C, Leung PCK. BMP-15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells. Mol Endocrinol. 2013;27(12):2093–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Albertini DF, et al. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction. 2001;121(5):647–53.

    Article  CAS  PubMed  Google Scholar 

  85. Grondahl ML, et al. Anti-Mullerian hormone remains highly expressed in human cumulus cells during the final stages of folliculogenesis. Reprod BioMed Online. 2011;22(4):389–98.

    Article  CAS  PubMed  Google Scholar 

  86. Dekel N, Kraicer PF. Induction in vitro of mucification of rat cumulus oophorus by gonadotrophins and adenosine 3′,5′-monophosphate. Endocrinology. 1978;102(6):1797–802.

    Article  CAS  PubMed  Google Scholar 

  87. Eppig JJ. Regulation of cumulus oophorus expansion by gonadotropins in vivo and in vitro. Biol Reprod. 1980;23(3):545–52.

    Article  CAS  PubMed  Google Scholar 

  88. Russell DL, Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update. 2007;13(3):289–312.

    Article  CAS  PubMed  Google Scholar 

  89. Fang L, Cheng JC, Chang HM, Sun YP, Leung PCK. EGF-like growth factors induce COX-2-derived PGE2 production through ERK1/2 in human granulosa cells. J Clin Endocrinol Metab. 2013;98(12):4932–41.

    Article  CAS  PubMed  Google Scholar 

  90. Russell DL, Salustri A. Extracellular matrix of the cumulus-oocyte complex. Semin Reprod Med. 2006;24(4):217–27.

    Article  CAS  PubMed  Google Scholar 

  91. Baranova NS, Inforzato A, Briggs DC, Tilakaratna V, Enghild JJ, Thakar D, et al. Incorporation of pentraxin 3 into hyaluronan matrices is tightly regulated and promotes matrix cross-linking. J Biol Chem. 2014;289(44):30481–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang H, Tian S, Klausen C, Zhu H, Liu R, Leung PCK. Differential activation of noncanonical SMAD2/SMAD3 signaling by bone morphogenetic proteins causes disproportionate induction of hyaluronan production in immortalized human granulosa cells. Mol Cell Endocrinol. 2016;428:17–27.

    Article  CAS  PubMed  Google Scholar 

  93. Hanrahan JP, Gregan SM, Mulsant P, Mullen M, Davis GH, Powell R, et al. Mutations in the genes for oocyte-derived growth factors GDF-9 and BMP-15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries). Biol Reprod. 2004;70(4):900–9.

    Article  CAS  PubMed  Google Scholar 

  94. Wu YT, et al. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum Reprod. 2007;22(6):1526–31.

    Article  CAS  PubMed  Google Scholar 

  95. Gode F, et al. Influence of follicular fluid GDF-9 and BMP-15 on embryo quality. Fertil Steril. 2011;95(7):2274–8.

    Article  CAS  PubMed  Google Scholar 

  96. Clementi C, et al. Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet. 2013;9(11):e1003863.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Nagashima T, et al. BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest. 2013;123(6):2539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Takebayashi K, et al. Mutation analysis of the growth differentiation factor-9 and -9B genes in patients with premature ovarian failure and polycystic ovary syndrome. Fertil Steril. 2000;74(5):976–9.

    Article  CAS  PubMed  Google Scholar 

  99. Crispi S, et al. Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. J Cell Physiol. 2013;228(9):1927–34.

    Article  CAS  PubMed  Google Scholar 

  100. Belli M, Shimasaki S. Molecular aspects and clinical relevance of GDF-9 and BMP-15 in ovarian function. Vitam Horm. 2018;107:317–48.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Tong S, Short RV. Dizygotic twinning as a measure of human fertility. Hum Reprod. 1998;13(1):95–8.

    Article  CAS  PubMed  Google Scholar 

  102. Zhao SY, et al. Expression of growth differentiation factor-9 and bone morphogenetic protein-15 in oocytes and cumulus granulosa cells of patients with polycystic ovary syndrome. Fertil Steril. 2010;94(1):261–7.

    Article  CAS  PubMed  Google Scholar 

  103. Dey SR, et al. Coculturing denuded oocytes during the in vitro maturation of bovine cumulus oocyte complexes exerts a synergistic effect on embryo development. Theriogenology. 2012;77(6):1064–77.

    Article  CAS  PubMed  Google Scholar 

  104. Oocyte-secreted factors in oocyte maturation media enhance subsequent development of bovine cloned embryos - Su - 2014 - Mol Reprod Dev - Wiley Online Library. 2018.

  105. Sudiman J, et al. Effects of differing oocyte-secreted factors during mouse in vitro maturation on subsequent embryo and fetal development. J Assist Reprod Genet. 2014;31(3):295–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yeo CX, et al. Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice. Hum Reprod. 2008;23(1):67–73.

    Article  CAS  PubMed  Google Scholar 

  107. Romaguera R, et al. Oocyte secreted factors improve embryo developmental competence of COCs from small follicles in prepubertal goats. Theriogenology. 2010;74(6):1050–9.

    Article  CAS  PubMed  Google Scholar 

  108. Gomez MN, et al. Effect of oocyte-secreted factors on porcine in vitro maturation, cumulus expansion and developmental competence of parthenotes. Zygote. 2012;20(2):135–45.

    Article  CAS  PubMed  Google Scholar 

  109. Ferrarini E, et al. Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. Maturitas. 2013;74(1):61–7.

    Article  CAS  PubMed  Google Scholar 

  110. Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol. 2010;45(5):257–79.

    Article  CAS  PubMed  Google Scholar 

  111. Tiotiu D, et al. Variants of the BMP-15 gene in a cohort of patients with premature ovarian failure. Hum Reprod. 2010;25(6):1581–7.

    Article  CAS  PubMed  Google Scholar 

  112. Auclair S, et al. Positive selection in bone morphogenetic protein 15 targets a natural mutation associated with primary ovarian insufficiency in human. PLoS One. 2013;8(10):e78199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Di Pasquale E, et al. Identification of new variants of human BMP-15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab. 2006;91(5):1976–9.

    Article  PubMed  CAS  Google Scholar 

  114. Kumar R, et al. BMP-15 and GDF-9 gene mutations in premature ovarian failure. J Reprod Infertil. 2017;18(1):185–9.

    PubMed  PubMed Central  Google Scholar 

  115. Patino LC, et al. BMP-15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with GDF-9. J Clin Endocrinol Metab. 2017;102(3):1009–19.

    PubMed  Google Scholar 

  116. Regan SL, et al. Dysregulation of granulosal bone morphogenetic protein receptor 1B density is associated with reduced ovarian reserve and the age-related decline in human fertility. Mol Cell Endocrinol. 2016;425:84–93.

    Article  CAS  PubMed  Google Scholar 

  117. Salehnia M, Pajokh M, Ghorbanmehr N. Short term organ culture of mouse ovary in the medium supplemented with bone morphogenetic protein 15 and follicle stimulating hormone: a morphological, hormonal and molecular study. J Reprod Infertil. 2016;17(4):199–207.

    PubMed  PubMed Central  Google Scholar 

  118. Devine PJ, Perreault SD, Luderer U. Roles of reactive oxygen species and antioxidants in ovarian toxicity. Biol Reprod. 2012;86(2):27.

    Article  PubMed  CAS  Google Scholar 

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Sanfins, A., Rodrigues, P. & Albertini, D.F. GDF-9 and BMP-15 direct the follicle symphony. J Assist Reprod Genet 35, 1741–1750 (2018). https://doi.org/10.1007/s10815-018-1268-4

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  • DOI: https://doi.org/10.1007/s10815-018-1268-4

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