Abstract
Naturally occurring mutations in the oocyte-specific factor, bone morphogenetic protein-15 (BMP-15), cause infertility in women and in ewes. In contrast to these monoovulatory mammals, the targeted deletion of BMP-15 in polyovulatory mice results in subfertility with only minimal defects in the ovulation process. Given the established role of BMP-15 in governing the progression of folliculogenesis, it is hypothesized that species-specific differences in the BMP-15 system are involved in species-specific determination of ovulation quota and litter size. Recent data using in vitro cell transfection methodology indicate that, in contrast to human BMP-15 which is successfully processed and secreted, the mouse BMP-15 proprotein is resistant to proteolytic cleavage. Thus, no functional mature BMP-15 is secreted in vitro. Further studies have shown that the functional mature form of BMP-15 is barely detectable in mouse oocytes in vivo until just before ovulation, when it is markedly increased. The general hypothesis to emerge from these observations is that the species-specific differences in the defects caused by mutations in the bmp 15 gene between monoovulatory ewes and women and polyovulatory mice might be attributed to the timing of the production of BMP-15 mature protein.
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References
Galloway SM, McNatty KP, Cambridge LM et al. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet 2000; 25: 279–283.
Hanrahan JP, Gregan SM, Mulsant P et al. 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: 900–909.
McNatty KP, Smith P, Moore LG et al. Oocyte-expressed genes affecting ovulation rate. Mol Cell Endocrinol 2005; 234: 57–66.
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: 557–561.
Juengel JL, Hudson NL, Heath DA et al. Growth differentiation factor-9 and bone morphogenetic protein 15 are essential for ovarian follicular development in sheep. Biol Reprod 2002; 67: 1777–1789.
Shimasaki S, Moore RK, Otsuka F, Erickson GF. The bone morphogenetic protein system in mammalian reproduction. Endocr Rev 2004; 25: 72–101.
Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004; 75: 106–111.
Yan C, Wang P, DeMayo J et al. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol 2001; 15: 854–866.
Eppig JJ, Wigglesworth K, Pendola F. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci USA 2002; 99: 2890–2894.
Hubner K, Fuhrmann G, Christenson LK et al. Derivation of oocytes from mouse embryonic stem cells. Science 2003; 300: 1251–1256.
Shimasaki S, Moore RK, Erickson GF, Otsuka F. The role of bone morphogenetic proteins in ovarian function. Reprod Supplement 2003; 61: 323–337.
Dube IL, Wang P, Elvin I, Lyons KM, Celeste AJ, Matzuk MM. The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol Endocrinol 1998; 12: 1809–1817.
Otsuka F, Yao Z, Lee TH, Yamamoto S, Erickson GF, Shimasaki S. Bone morphogenetic protein-15: Identification of target cells and biological functions. J Biol Chem 2000; 275: 39 523–39 528.
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: 11 387–11 392.
Otsuka F, Moore RK, Iemura S-I, Ueno N, Shimasaki S. Follistatin inhibits the function of the oocyte-derived factor BMP-15. Biochem Biophys Res Commun 2001; 289: 961–966.
Otsuka F, Shimasaki S. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis. Proc Natl Acad Sci USA 2002; 99: 8060–8065.
Otsuka F, Shimasaki S. A novel function of bone morphogenetic protein-15 in the pituitary: selective synthesis and secretion of FSH by gonadotropes. Endocrinology 2002; 143: 4938–4941.
Moore RK, Otsuka F, Shimasaki S. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J Biol Chem 2003; 278: 304–310.
Liao WX, Moore RK, Otsuka F, Shimasaki S. Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiaton factor-9: Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. J Biol Chem 2003; 278: 3713–3719.
Liao WX, Moore RK, Shimasaki S. Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors BMP-15 and GDF-9. J Biol Chem 2004; 279: 17 391–17 396.
Yoshino O, McMahon HE, Sharma S, Shimasaki S. A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse. Proceedings of the Natl Acad Sci 2006; 103: 10 678–10 683.
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 2005; 102: 5426–5431.
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An erratum to this article is available at http://dx.doi.org/10.1111/j.1447-0578.2007.00166.x.
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Shimasaki, S. BMP-15 regulation of ovulation quota in mammals. Reprod Med Biol 5, 245–248 (2006). https://doi.org/10.1111/j.1447-0578.2006.00148.x
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DOI: https://doi.org/10.1111/j.1447-0578.2006.00148.x