The Effect of BMP15 and GDF9 Gene Mutations on Follicular Development and Ovulation in Mouse (Mus musculus) and Sheep (Ovis aries)
WANG Xiang-Yu, DI Ran, LIU Qiu-Yue, HU Wen-Ping, MA Lin, CHU Ming-Xing*
Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
Abstract：In mammalian ovary, folliculogenesis, development and follicle maturation toward ovulation is a complex biological process. This process requires the precise coordination of oocyte and its companion somatic cells. During this process, oocyte-secreted factors bone morphogenetic protein 15 (BMP15) and growth differentiation factors 9 (GDF9) regulate granulosa cells growth, differentiation, promote folliculogenesis from the primordial stage, determine ovulatory follicle survival and ultimately affect ovulation by paracrine/autocrine mechanisms. It has been found that mutations of the BMP15 and GDF9 gene cause the distinct alteration in ovarian function in different species. In mice (Mus musculus) , homozygous null mutation of BMP15 reduce the fertility of female mice, but GDF9-nulll female mice are sterility. In sheep (Ovis aries), heterozygous mutant of these two genes decrease the BMP signaling and lead to the hyper prolificacy, whereas the homozygous sheep exhibit the inhibition of ovarian follicular development and infertility. In this review, we described the changes of ovarian function and ovulation in BMP15/GDF9 knockout and overexpressing mice and sheep with natural mutations. We summarized that BMP15, GDF9 and their dimmers orchestrate follicular development, participant in selection of dominant follicular and regulate ovulation by the dynamic balance of their bioactivity. The recent findings relating the functions of BMP15 and GDF9 opened up new perspectives for regulation of sheep ovulation and breeding new prolific sheep.
王翔宇, 狄冉, 刘秋月, 胡文萍, 马琳, 储明星. 小鼠和绵羊BMP15和GDF9突变在卵泡发育中作用及其对排卵数的影响[J]. 农业生物技术学报, 2020, 28(10): 1870-1880.
WANG Xiang-Yu, DI Ran, LIU Qiu-Yue, HU Wen-Ping, MA Lin, CHU Ming-Xing. The Effect of BMP15 and GDF9 Gene Mutations on Follicular Development and Ovulation in Mouse (Mus musculus) and Sheep (Ovis aries). 农业生物技术学报, 2020, 28(10): 1870-1880.
[1] Anderson E, Albertini D F.1976. Gap junctions between the oocyte and companion follicle cells in the mammalian ovary[J]. The Journal of Cell Biology, 71(2): 680-686. [2] Belli M. Shimasaki S.2018. Chapter Twelve - Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function[J]. Vitamins and Hormones, 107: 317-348. [3] Bodensteiner K, Clay J C M, Moeller C L, et al.1999. Molecular cloning of the ovine growth/differentiation factor-9 gene and expression of growth/differentiation factor-9 in ovine and bovine ovaries[J]. Biology of reproduction, 60(2): 381-386. [4] Bodin L, Di Pasquale E, Fabre S, et al.2007. A novel mutation in the bone morphogenetic protein 15 gene causing defective protein secretion is associated with both increased ovulation rate and sterility in lacaune sheep[J]. Endocrinology, 148(1): 393-400. [5] Carabatsos M, Elvin J J, Matzuk M M, et al.1998. Characterization of oocyte and follicle development in growth differentiation factor-9-deficient mice[J]. Developmental Biology, 204(2): 373-384. [6] Chang H. Qiao J, Leung P C K.2016. Oocyte-somatic cell interactions in the human ovary--novel role of bone morphogenetic proteins and growth differentiation factors[J]. Human Reproduction Update, 23(1): 1-18. [7] Clarke H J.2017. Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle[J]. Wiley Interdisciplinary Reviews: Developmental Biology, 7(1): e294. [8] Del Collado M, Andrade G M, Meirelles F V, et al.2018. Contributions from the ovarian follicular environment to oocyte function[J]. Animal Reproduction, 15(3): 261-270. [9] Demars J, Fabre S, Sarry J, et al.2013. Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep[J]. PLoS Genetics, 9(4): e1003482. [10] Derek A H, Janet L P, Kenneth P M.2017. Molecular forms of ruminant BMP15 and GDF9 and putative interactions with receptors[J]. Reproduction, 154(4): 521-534. [11] Di Pasquale E, Beck-Peccoz P, Persani L.2004. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene[J]. American Journal of Human Genetics, 75(1): 106-111. [12] Dong J, Albertini D F, Nishimori K, et al.1996. Growth differentiation factor-9 is required during early ovarian folliculogenesis[J]. Nature, 383(6600): 531-535. [13] Dube J L, Wang P, Elvin J, et al.1998. The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes[J]. Molecular Endocrinology, 12(12): 1809-1817. [14] El-Hayek S, Yang Q, Abbassi L, et al.2018. Mammalian Oocytes Locally Remodel Follicular Architecture to Provide the Foundation for Germline-Soma Communication[J]. Current Biology, 28(7): 1124-1131. [15] El-Hayek S, Clarke H J.2016. Control of Oocyte Growth and Development by Intercellular Communication Within the Follicular Niche[M]//Molecular Mechanisms of Cell Differentiation in Gonad Development. Piprek R P eds, Cham, Springer International Publishing. vol 58, pp. 191-224. [16] ElvinJ A, Yan C, Wang P, et al.1999. Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary[J]. Molecular Endocrinology, 13(6): 1018-1034. [17] Eppig J J.2018. Reproduction: Oocytes call, granulosa cells connect[J]. Current Biology, 28(8): R354-R356. [18] Fabre S, Pierre A, Mulsant P, et al.2006. Regulation of ovulation rate in mammals: Contribution of sheep genetic models[J]. Reproductive Biology and Endocrinology, 4: 20. [19] Fenwick M A, Mora J M, Mansour Y T, et al.2013. Investigations of TGF-β signaling in preantral follicles of female mice reveal differential roles for bone morphogenetic protein 15[J]. Endocrinology, 154(9): 3423-3436. [20] Galloway S M, McNatty K P, Cambridge L M, et al.2000. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner[J]. Nature Genetics, 25(3): 279-283. [21] Hanrahan J P, Gregan S M, Mulsant P, et al.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)[J]. Biology of Reproduction, 70(4): 900-909. [22] Harrison C A, Al-Musawi S L, Walton K L.2011. Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands[J]. Growth Factors, 29(5): 174-186. [23] Juengel J L.2018. How the quest to improve sheep reproduction provided insight into oocyte control of follicular development[J]. Journal of the Royal Society of New Zealand, 48(2-3): 143-163. [24] Juengel J L, Bodensteiner K J, Heath D A, et al.2004. Physiology of GDF9 and BMP15 signalling molecules[J]. Animal Reproduction Science, 82-83: 447-460. [25] Juengel J L, McNatty K P.2005. The role of proteins of the transforming growth factor-beta superfamily in the intraovarian regulation of follicular development[J]. Human Reproduction Update, 11(2): 143-160. [26] Kaivo-Oja N, Mottershead D G, Mazerbourg S, et al.2005. Adenoviral gene transfer allows Smad-responsive gene promoter analyses and delineation of type I receptor usage of transforming growth factor-beta family ligands in cultured human granulosa luteal cells[J]. The Journal of Clinical Endocrinology & Metabolism, 90(1): 271-278. [27] Laitinen M, Vuojolainen K, Jaatinen R, et al.1998. A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis[J]. Mechanisms of Development, 78(1): 135-140. [28] Lassoued N, Benkhlil Z,Woloszyn F, et al.2017. FecXBara Novel BMP15 mutation responsible for prolificacy and female sterility in Tunisian Barbarine Sheep[J]. BMC Genetics, 18(1): 43. [29] Li Q, Pangas S A, Jorgez C J, et al.2008. Redundant roles of SMAD2 and SMAD3 in ovarian granulosa cells in vivo[J]. Molecular and Cellular Biology, 28(23): 7001-7011. [30] Li Y, Li R Q, Ou S B, et al.2014. Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans[J]. Reproductive Biology and Endocrinology, 12: 81. [31] Liao W X, Moore R K, Shimasaki S.2004. Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9[J]. The Journal of Biological Chemistry, 279(17): 17391-17396. [32] Linda N, Stephen C B, Ricardo P, et al.2009. Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep[J]. Reproduciton, 138(6): 921-933. [33] Liu C, Peng J, Matzuk M M, et al.2015. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells[J]. Nature Communications, 6: 6934. [34] Liu Q, Pan Z, Wang X, et al.2014. Progress on major genes for high fecundity in ewes[J]. Frontiers of Agricultural Science and Engineering, 1(4): 282-290. [35] Martinez-Royo A, Jurado J J, Smulders J P, et al.2008. A deletion in the bone morphogenetic protein 15 gene causes sterility and increased prolificacy in Rasa Aragonesa sheep[J]. Animal Genetics, 39(3): 294-297. [36] Matzuk M M, Burns K H, Viveiros M M, et al.2002. Intercellular communication in the mammalian ovary: Oocytes carry the conversation[J]. Science, 296(5576): 2178-2180. [37] Mazerbourg S, Klein C, Roh J, et al.2004. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5[J]. Molecular Endocrinology, 18(3): 653-665. [38] McIntosh C J, Lun S, Lawrence S, et al.2008. The proregion of mouse BMP15 regulates the cooperative interactions of BMP15 and GDF9[J]. Biology of Reproduction, 79(5): 889-896. [39] McMahon H E, Hashimoto O, Mellon P L, et al.2008. Oocyte-specific overexpression of mouse bone morphogenetic protein-15 leads to accelerated folliculogenesis and an early onset of acyclicity in transgenic mice[J]. Endocrinology, 149(6): 2807-2815. [40] McNatty K, Smith P P, Moore L G, et al.2005. Oocyte-expressed genes affecting ovulation rate[J]. Molecular and Cellular Endocrinology, 234(1): 57-66. [41] McPherron A C, Lee S J.1993. GDF-3 and GDF-9: Two new members of the transforming growth factor-β superfamily containing a novel pattern of cysteines[J]. Journal of Biological Chemistry, 268(5): 3444-3449. [42] Melo E O, Silva B D, Castro E A, et al.2008. A novel mutation in the growth and differentiation factor 9 (GDF9) Gene is associated, in homozygosis, with increased ovulation rate in santa ines sheep.[J]. Biology of Reproduction, 78(Suppl_1): 141-142. [43] Monestier O, Servin B, Auclair S, et al.2014. Evolutionary origin of bone morphogenetic protein 15 and growth and differentiation factor 9 and differential selective pressure between mono- and polyovulating species[J]. Biology of Reproduction, 91(4): 1-13. [44] Monniaux D.2016. Driving folliculogenesis by the oocyte-somatic cell dialog: Lessons from genetic models[J]. Theriogenology, 86(1): 41-53. [45] Monteagudo L V, Ponz R, Tejedor M T, et al.2009. A 17 bp deletion in the Bone Morphogenetic Protein 15 (BMP15) gene is associated to increased prolificacy in the Rasa Aragonesa sheep breed[J]. Animal Reproduction Science, 110(1-2): 139-146. [46] Moore R K, Otsuka F, Shimasaki S.2003. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells[J]. The Journal of Biological Chemistry, 278(1): 304-310. [47] Mottershead D G, Ritter L J, Gilchrist R B.2012. Signalling pathways mediating specific synergistic interactions between GDF9 and BMP15[J]. Molecular Human Reproduction, 18(3): 121-128. [48] Mottershead D G, Sugimura S, Al-Musawi S L, et al.2015. Cumulin, an oocyte-secreted heterodimer of the transforming growth factor-β family, is a potent activator of granulosa cells and improves oocyte quality[J]. The Journal of Biological Chemistry, 290(39): 24007-24020. [49] Mullen M P, Hanrahan J P.2014. Direct evidence on the contribution of a missense mutation in GDF9 to variation in ovulation rate of Finnsheep[J]. PLOS ONE, 9(4): e95251. [50] Otsuka F, McTavish K J, Shimasaki S.2011. Integral role of GDF-9 and BMP-15 in ovarian function[J]. Molecular Reproduction and Development, 78(1): 9-21. [51] Otsuka F,Shimasaki S.2002. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: Its role in regulating granulosa cell mitosis[J]. Proceedings of the National Academy of Sciences of the USA, 99(12): 8060-8065. [52] Peng J, Li Q, Wigglesworth K, et al.2013. Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions[J]. Proceedings of the National Academy of Sciences of the USA, 110(8): E776-E785. [53] Persani L, Rossetti R, Di Pasquale E, et al.2014. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders[J]. Human Reproduction Update, 20(6): 869-883. [54] Pulkki M M, Mottershead D G, Pasternack A H, et al.2012. A covalently dimerized recombinant human bone morphogenetic protein-15 variant identifies bone morphogenetic protein receptor type 1B as a key cell surface receptor on ovarian granulosa cells[J]. Endocrinology, 153(3): 1509-1518. [55] Rankin T, Soyal S, Dean J.2000. The mouse zona pellucida: folliculogenesis, fertility and pre-implantation development[J]. Molecular and Cellular Endocrinology, 163(1): 21-25. [56] Richani D, Gilchrist R B.2018. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence[J]. Human Reproduction Update, 24(1): 1-14. [57] Robker R L, Hennebold J D, Russell D L.2018. Coordination of ovulation and oocyte maturation: A good egg at the right time[J]. Endocrinology, 159(9): 3209-3218. [58] Scaramuzzi R J, Baird D T, Campbell B K, et al.2011. Regulation of folliculogenesis and the determination of ovulation rate in ruminants[J]. Reproduction, Fertility and Development, 23(3): 444-467. [59] Sela-Abramovich S, Edry I, Galiani D, et al.2006. Disruption of gap junctional communication within the ovarian follicle induces oocyte maturation[J]. Endocrinology, 147(5): 2280-2286. [60] Shi Y, Massagué J.2003. Mechanisms of TGF-β signaling from cell membrane to the nucleus[J]. Cell, 113(6): 685-700. [61] Shimasaki S, Moore R K, Otsuka F, et al.2004. The bone morphogenetic protein system in mammalian reproduction[J]. Endocrine Reviews, 25(1): 72-101. [62] Sidis Y, Fujiwara T, Leykin L, et al.1998. Characterization of inhibin/activin subunit, activin receptor, and follistatin messenger ribonucleic acid in human and mouse oocytes: evidence for activin's paracrine signaling from granulosa cells to oocytes[J]. Biology of Reproduction, 59(4): 807-812. [63] Silva B D M, Castro E A, Souza C J H, et al.2011. A new polymorphism in the growth and differentiation factor 9 (GDF9) gene is associated with increased ovulation rate and prolificacy in homozygous sheep[J]. Animal Genetics, 42(1): 89-92. [64] Souza C J H, McNeilly A S, Benavides M V, et al.2014. Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes[J]. Animal Genetics, 45(5): 732-739. [65] Su Y Q, Sugiura K, Wigglesworth K, et al.2008. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells[J]. Development, 135(1): 111-121. [66] Su Y Q, Sugiura K, Eppig J J.2009. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism[J]. Seminars in Reproductive Medicine, 27(1): 32-42. [67] Su Y, Wu X, O'Brien M J, et al.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[J]. Developmental Biology, 276(1): 64-73. [68] Sugiura K, Su Y, Diaz F J, et al.2007. Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells[J]. Development, 134(14): 2593-2603. [69] Sun R Z, Lei L,Cheng L, et al.2010. Expression of GDF-9, BMP-15 and their receptors in mammalian ovary follicles[J]. Journal of Molecular Histology, 41(6): 325-332. [70] Våge D I, Husdal M, Kent M P, et al.2013. A missense mutation in growth differentiation factor 9 (GDF9) is strongly associated with litter size in sheep[J]. BMC Genetics, 14(1): 1. [71] Veitia R A, Caburet S.2009. Extensive sequence turnover of the signal peptides of members of the GDF/BMP family: Exploring their evolutionary landscape[J]. Biology direct, 4: 22. [72] Yan C, Wang P, DeMayo J, et al.2001. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function[J]. Molecular Endocrinology, 15(6): 854-866. [73] Yoshino O, McMahon H E, Sharma S, et al.2006. A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse[J]. Proceedings of the National Academy of Sciences of the USA, 103(28): 10678-10683. [74] Zhang M, Su Y, Sugiura K, et al.2010. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes[J]. Science, 330(6002): 366-369. [75] Zhang Y, Yan Z, Qin Q, et al.2018. Transcriptome landscape of human folliculogenesis reveals oocyte and granulosa cell interactions[J]. Molecular Cell, 72(6): 1021-1034.
