Animal Reproduction (AR)
Animal Reproduction (AR)

Local regulation of antral follicle development and ovulation in monovulatory species

Fabiane Pereira de Moraes; Daniele Missio; Jessica Lazzari; Monique Tomazele Rovani; Rogério Ferreira; Paulo Bayard Dias Gonçalves; Bernardo Garziera Gasperin

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The identification of mutations in the genes encoding bone morphogenetic protein 15 (BMP15) and growth and differentiation factor 9 (GDF9) associated with phenotypes of sterility or increased ovulation rate in sheep aroused interest in the study of the role of local factors in preantral and antral folliculogenesis in different species. An additive mutation in the BMP15 receptor, BMPR1b, which determines an increase in the ovulatory rate, has been introduced in several sheep breeds to increase the number of lambs born. Although these mutations indicate extremely relevant functions of these factors, the literature data on the regulation of the expression and function of these proteins and their receptors are very controversial, possibly due to differences in experimental models. The present review discusses the published data and preliminary results obtained by our group on the participation of local factors in the selection of the dominant follicle, ovulation, and follicular atresia in cattle, focusing on transforming growth factors beta and their receptors. The study of the expression pattern and the functionality of proteins produced by follicular cells and their receptors will allow increasing the knowledge about this local system, known to be involved in ovarian physiopathology and with the potential to promote contraception or increase the ovulation rate in mammals.


oocyte, deviation, transforming growth factors


Akiyama I, Yoshino O, Osuga Y, Shi J, Takamura M, Harada M, Koga K, Hirota Y, Hirata T, Fujii T, Saito S, Kozuma S. The role of bone morphogenetic protein 6 in accumulation and regulation of neutrophils in the human ovary. Reprod Sci. 2014;21(6):772-7. PMid:24406789.

Alam MH, Lee J, Miyano T. GDF9 and BMP15 induce development of antrum-like structures by bovine granulosa cells without oocytes. J Reprod Dev. 2018;64(5):423-31. PMid:30033985.

Alam MH, Miyano T. Interaction between growing oocytes and granulosa cells in vitro. Reprod Med Biol. 2020;19(1):13-23. PMid:31956281.

Belli M, Shimasaki S. Molecular aspects and clinical relevance of GDF9 and BMP15 in ovarian function. Vitam Horm. 2018;107:317-48. PMid:29544636.

Caixeta ES, Ripamonte P, Franco MM, Junior JB, Dode MAN. Effect of follicle size on mRNA expression in cumulus cells and oocytes of Bos indicus: an approach to identify marker genes for developmental competence. Reprod Fertil Dev. 2009;21(5):655-64. PMid:19486602.

Crawford JL, McNatty KP. The ratio of growth differentiation factor 9: bone morphogenetic protein 15 mRNA expression is tightly co-regulated and differs between species over a wide range of ovulation rates. Mol Cell Endocrinol. 2012;348(1):339-43. PMid:21970812.

Davis KA, Klohonatz KM, Mora DSO, Twenter HM, Graham PE, Pinedo P, Eckery DC, Bruemmer JE. Effects of immunization against bone morphogenetic protein-15 and growth differentiation factor-9 on ovarian function in mares. Anim Reprod Sci. 2018;192:69-77. PMid:29534827.

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. PMid:8849725.

Donnison M, Pfeffer PL. Isolation of genes associated with developmentally competent bovine oocytes and quantitation of their levels during development. Biol Reprod. 2004;71(6):1813-21. PMid:15286031.

Edson MA, Nalam RL, Clementi C, Franco HL, DeMayo FJ, Lyons KM, Pangas SA, Matzuk MM. Granulosa cell-expressed BMPR1A and BMPR1B have unique functions in regulating fertility but act redundantly to suppress ovarian tumor development. Mol Endocrinol. 2010;24(6):1251-66. PMid:20363875.

Galloway SM, McNatty KP, Cambridge LM, Laitinen MPE, Juengel JL, Jokiranta TS, McLaren RJ, Luiro K, Dodds KG, Montgomery GW, Beattie AE, Davis GH, Ritvos O. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet. 2000;25(3):279-83. PMid:10888873.

Garcia-Guerra A, Kamalludin MH, Kirkpatrick BW, Wiltbank MC. Trio a novel bovine high-fecundity allele: II. Hormonal profile and follicular dynamics underlying the high ovulation rate. Biol Reprod. 2018a;98(3):335-49. PMid:29425274.

Garcia-Guerra A, Wiltbank MC, Battista SE, Kirkpatrick BW, Sartori R. Mechanisms regulating follicle selection in ruminants: lessons learned from multiple ovulation models. Anim Reprod. 2018b;15(1, Suppl 1):660-79. PMid:36249844.

Gasperin BG, Ferreira R, Rovani MT, Bordignon V, Duggavathi R, Buratini J, Oliveira JFC, Gonçalves PBD. Expression of receptors for BMP15 is differentially regulated in dominant and subordinate follicles during follicle deviation in cattle. Anim Reprod Sci. 2014;144(3-4):72-8. PMid:24388700.

Glister C, Kemp CF, Knight PG. Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin. Reproduction. 2004;127(2):239-54. PMid:15056790.

Glister C, Richards SL, Knight PG. Bone Morphogenetic Proteins (BMP) -4, -6, and -7 potently suppress basal and luteinizing hormone-induced androgen production by bovine theca interna cells in primary culture: could ovarian hyperandrogenic dysfunction be caused by a defect in thecal bmp signaling? Endocrinology. 2005;146(4):1883-92. PMid:15625241.

Glister C, Satchell L, Knight PG. Changes in expression of bone morphogenetic proteins (BMPs), their receptors and inhibin co-receptor betaglycan during bovine antral follicle development: inhibin can antagonize the suppressive effect of BMPs on thecal androgen production. Reproduction. 2010;140(5):699-712. PMid:20739376.

Haas CS, Oliveira FC, Rovani MT, Ferst JG, Vargas SF Jr, Vieira AD, Mondadori RG, Pegoraro LMC, Gonçalves PBD, Bordignon V, Ferreira R, Gasperin BG. Bone morphogenetic protein 15 intrafollicular injection inhibits ovulation in cattle. Theriogenology. 2022;182:148-54. PMid:35176680.

Haas CS, Rovani MT, Oliveira FC, Vieira AD, Bordignon V, Gonçalves PBD, Ferreira R, Gasperin BG. Expression of growth and differentiation Factor 9 and cognate receptors during final follicular growth in cattle. Anim Reprod. 2016;13(4):756-61.

Hanrahan JP, Gregan SM, Mulsant P, Mullen M, Davis GH, Powell R, Galloway SM. 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. 2004;70(4):900-9. PMid:14627550.

Heath DA, Pitman JL, McNatty KP. Molecular forms of ruminant BMP15 and GDF9 and putative interactions with receptors. Reproduction. 2017;154(4):521-34. PMid:28733348.

Hoyos-Marulanda V, Haas CS, Goularte KL, Rovani MT, Mondadori RG, Vieira AD, Gasperin BG, Lucia T Jr. Expression of steroidogenic enzymes and TGFβ superfamily members in follicular cells of prepubertal gilts with distinct endocrine profiles. Zygote. 2022;30(1):65-71. PMid:33966679.

Huang Z, Wells D. The human oocyte and cumulus cells relationship: new insights from the cumulus cell transcriptome. Mol Hum Reprod. 2010;16(10):715-25. PMid:20435609.

Ilha GF, Rovani MT, Gasperin BG, Ferreira R, Macedo MP, Neto OA, Duggavathi R, Bordignon V, Gonçalves PBD. Regulation of Anti‐Müllerian hormone and its receptor expression around follicle deviation in cattle. Reprod Domest Anim. 2016;51(2):188-94. PMid:26815645.

Jayawardana BC, Shimizu T, Nishimoto H, Kaneko E, Tetsuka M, Miyamoto A. Hormonal regulation of expression of growth differentiation factor-9 receptor type I and II genes in the bovine ovarian follicle. Reproduction. 2006;131(3):545-53. PMid:16514197.

Juengel JL, Hudson NL, Berg M, Hamel K, Smith P, Lawrence SB, Whiting L, McNatty KP. Effects of active immunization against growth differentiation factor 9 and/or bone morphogenetic protein 15 on ovarian function in cattle. Reproduction. 2009;138(1):107-14. PMid:19439562.

Juengel JL, Hudson NL, Whiting L, McNatty KP. Effects of immunization against bone morphogenetic protein 15 and growth differentiation factor 9 on ovulation rate, fertilization, and pregnancy in ewes. Biol Reprod. 2004;70(3):557-61. PMid:14585806.

Juengel JL, Quirke LD, Tisdall DJ, Smith P, Hudson NL, McNatty KP. Gene expression in abnormal ovarian structures of ewes homozygous for the inverdale prolificacy gene. Biol Reprod. 2000;62(6):1467-78. PMid:10819746.

Juengel JL, Reader KL, Bibby AH, Lun S, Ross I, Haydon LJ, McNatty KP. The role of bone morphogenetic proteins 2, 4, 6 and 7 during ovarian follicular development in sheep: contrast to rat. Reproduction. 2006;131(3):501-13. PMid:16514193.

Kathirvel M, Soundian E, Kumanan V. Differential expression dynamics of Growth differentiation factor9 (GDF9) and Bone morphogenetic factor15 (BMP15) mRNA transcripts during in vitro maturation of buffalo (Bubalus bubalis) cumulus-oocyte complexes. Springerplus. 2013;2(1):206. PMid:23724366.

Kayani AR, Glister C, Knight PG. Evidence for an inhibitory role of bone morphogenetic protein(s) in the follicular-luteal transition in cattle. Reproduction. 2009;137(1):67-78. PMid:18936084.

Knight PG, Glister C. TGF-β superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191-206. PMid:16885529.

Li Y, Li RQ, Ou SB, Zhang NF, Ren L, Wei LN, Zhang QX, Yang DZ. Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans. Reprod Biol Endocrinol. 2014;12(1):81. PMid:25139161.

Matsui M, Sonntag B, Hwang SS, Byerly T, Hourvitz A, Adashi EY, Shimasaki S, Erickson GF. Pregnancy-associated plasma protein-a production in rat granulosa cells: stimulation by follicle-stimulating hormone and inhibition by the oocyte-derived bone morphogenetic protein-15. Endocrinology. 2004;145(8):3686-95. PMid:15087430.

McNatty KP, Heath DA, Hudson NL, Lun S, Juengel JL, Moore LG. Gonadotrophin-responsiveness of granulosa cells from bone morphogenetic protein 15 heterozygous mutant sheep. Reproduction. 2009;138(3):545-51. PMid:19535491.

McNatty KP, Hudson NL, Whiting L, Reader KL, Lun S, Western A, Heath DA, Smith P, Moore LG, Juengel JL. The effects of immunizing sheep with different BMP15 or GDF9 peptide sequences on ovarian follicular activity and ovulation rate. Biol Reprod. 2007;76(4):552-60. PMid:17093201.

McNatty KP, Juengel JL, Reader KL, Lun S, Myllymaa S, Lawrence SB, Western A, Meerasahib MF, Mottershead DG, Groome NP, Ritvos O, Laitinen MPE. Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction. 2005;129(4):481-7. PMid:15798023.

McNatty KP, Moore LG, Hudson NL, Quirke LD, Lawrence SB, Reader K, Hanrahan JP, Smith P, Groome NP, Laitinen M, Ritvos O, Juengel JL. The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction. 2004;128(4):379-86. PMid:15454632.

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. PMid:21226076.

Otsuka F, Yamamoto S, Erickson GF, Shimasaki S. Bone morphogenetic protein-15 inhibits Follicle-Stimulating Hormone (FSH) action by suppressing FSH receptor expression. J Biol Chem. 2001;276(14):11387-92. PMid:11154695.

Park MJ, Ahn JW, Kim KH, Bang J, Kim SC, Jeong JY, Choi YE, Kim CW, Joo BS. Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT. Exp Biol Med (Maywood). 2020;245(8):711-9. PMid:32223330.

Patiño LC, Walton KL, Mueller TD, Johnson KE, Stocker W, Richani D, Agapiou D, Gilchrist RB, Laissue P, Harrison CA. BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with GDF9. J Clin Endocrinol Metab. 2017;102(3):1009-19. PMid:28359091.

Paulini F, Melo EO. Effects of Growth and Differentiation Factor 9 and Bone Morphogenetic Protein 15 overexpression on the steroidogenic metabolism in bovine granulosa cells in vitro. Reprod Domest Anim. 2021;56(6):837-47. PMid:33683747.

Paulini F, Melo EO. The role of oocyte-secreted factors GDF9 and BMP15 in follicular development and oogenesis. Reprod Domest Anim. 2011;46(2):354-61. PMid:21198974.

Rossi RODS, Costa JJN, Silva AWB, Saraiva MVA, Van Den Hurk R, Silva JRV. The bone morphogenetic protein system and the regulation of ovarian follicle development in mammals. Zygote. 2016;24(1):1-17. PMid:25613521.

Rovani MT, Gasperin BG, Ferreira R, Duggavathi R, Bordignon V, Gonçalves PBD. Methods to study ovarian function in monovulatory species using the cow as a model. Anim Reprod. 2018;14(2):383-91.

Sanfins A, Rodrigues P, Albertini DF. GDF-9 and BMP-15 direct the follicle symphony. J Assist Reprod Genet. 2018;35(10):1741-50. PMid:30039232.

Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113(6):685-700. PMid:12809600.

Spicer LJ, Aad PY, Allen D, Mazerbourg S, Hsueh AJ. Growth differentiation factor-9 has divergent effects on proliferation and steroidogenesis of bovine granulosa cells. J Endocrinol. 2006;189(2):329-39. PMid:16648300.

Spicer LJ, Aad PY, Allen DT, Mazerbourg S, Payne AH, Hsueh AJ. Growth Differentiation Factor 9 (GDF9) stimulates proliferation and inhibits steroidogenesis by bovine theca cells: influence of follicle size on responses to GDF9. Biol Reprod. 2008;78(2):243-53. PMid:17959852.

Yan C, Wang P, DeMayo J, DeMayo FJ, Elvin JA, Carino C, Prasad SV, Skinner SS, Dunbar BS, Dube JL, Celeste AJ, Matzuk MM. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol. 2001;15(6):854-66. PMid:11376106.

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