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Synergistic Roles of Bone Morphogenetic Protein 15 and Growth Differentiation Factor 9 in Ovarian Function

Departments of Pathology (C.Y., M.M.M.), Molecular and Cellular Biology (P.W., J.D., F.J.D., C.C., S.V.P., S.S.S., B.S.D., M.M.M.), and Molecular and Human Genetics (J.A.E., M.M.M.) Baylor College of Medicine Houston, Texas, 77030
Department of Tissue Growth and Repair (J.L.D., A.J.C.) Genetics Institute, Inc. Cambridge, Massachusetts 02140

Knockout mouse technology has been used over the last decade to define the essential roles of ovarian-expressed genes and uncover genetic interactions. In particular, we have used this technology to study the function of multiple members of the transforming growth factor-ß superfamily including inhibins, activins, and growth differentiation factor 9 (GDF-9 or Gdf9). Knockout mice lacking GDF-9 are infertile due to a block in folliculogenesis at the primary follicle stage. In addition, recombinant GDF-9 regulates multiple cumulus granulosa cell functions in the periovulatory period including hyaluronic acid synthesis and cumulus expansion. We have also cloned an oocyte-specific homolog of GDF-9 from mice and humans, which is termed bone morphogenetic protein 15 (BMP-15 or Bmp15). To define the function of BMP-15 in mice, we generated embryonic stem cells and knockout mice, which have a null mutation in this X-linked gene. Male chimeric and Bmp15 null mice are normal and fertile. In contrast to Bmp15 null males and Gdf9 knockout females, Bmp15 null females (Bmp15^-/-) are subfertile and usually have minimal ovarian histopathological defects, but demonstrate decreased ovulation and fertilization rates. To further decipher possible direct or indirect genetic interactions between GDF-9 and BMP-15, we have generated double mutant mice lacking one or both alleles of these related homologs. Double homozygote females (Bmp15^-/-Gdf9^-/-) display oocyte loss and cysts and resemble Gdf9^-/- mutants. In contrast, Bmp15^-/-Gdf9^+/- female mice have more severe fertility defects than Bmp15^-/- females, which appear to be due to abnormalities in ovarian folliculogenesis, cumulus cell physiology, and fertilization. Thus, the dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during folliculogenesis and in the periovulatory period. These studies have important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.

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				G. A. R. Maciel, E. C. Baracat, J. A. Benda, S. M. Markham, K. Hensinger, R. J. Chang, and G. F. Erickson Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5321 - 5327. [Abstract] [Full Text] [PDF]

				K P McNatty, L G Moore, N L Hudson, L D Quirke, S B Lawrence, K Reader, J P Hanrahan, P Smith, N P Groome, M Laitinen, et al. The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology Reproduction, October 1, 2004; 128(4): 379 - 386. [Abstract] [Full Text] [PDF]

				S. Pennetier, S. Uzbekova, C. Perreau, P. Papillier, P. Mermillod, and R. Dalbies-Tran Spatio-Temporal Expression of the Germ Cell Marker Genes MATER, ZAR1, GDF9, BMP15,andVASA in Adult Bovine Tissues, Oocytes, and Preimplantation Embryos Biol Reprod, October 1, 2004; 71(4): 1359 - 1366. [Abstract] [Full Text] [PDF]

				J. Yao, X. Ren, J. J. Ireland, P. M. Coussens, T. P. L. Smith, and G. W. Smith Generation of a bovine oocyte cDNA library and microarray: resources for identification of genes important for follicular development and early embryogenesis Physiol Genomics, September 16, 2004; 19(1): 84 - 92. [Abstract] [Full Text] [PDF]

				D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]

				R.B. Gilchrist, L.J. Ritter, M. Cranfield, L.A. Jeffery, F. Amato, S.J. Scott, S. Myllymaa, N. Kaivo-Oja, H. Lankinen, D.G. Mottershead, et al. Immunoneutralization of Growth Differentiation Factor 9 Reveals It Partially Accounts for Mouse Oocyte Mitogenic Activity Biol Reprod, September 1, 2004; 71(3): 732 - 739. [Abstract] [Full Text] [PDF]

				S. Sudo, O. Avsian-Kretchmer, L. S. Wang, and A. J. W. Hsueh Protein Related to DAN and Cerberus Is a Bone Morphogenetic Protein Antagonist That Participates in Ovarian Paracrine Regulation J. Biol. Chem., May 28, 2004; 279(22): 23134 - 23141. [Abstract] [Full Text] [PDF]

				J. D. Hennebold Characterization of the ovarian transcriptome through the use of differential analysis of gene expression methodologies Hum. Reprod. Update, May 1, 2004; 10(3): 227 - 239. [Abstract] [Full Text] [PDF]

				W. X. Liao, R. K. Moore, and S. Shimasaki Functional and Molecular Characterization of Naturally Occurring Mutations in the Oocyte-secreted Factors Bone Morphogenetic Protein-15 and Growth and Differentiation Factor-9 J. Biol. Chem., April 23, 2004; 279(17): 17391 - 17396. [Abstract] [Full Text] [PDF]

				C. J. Jorgez, M. Klysik, S. P. Jamin, R. R. Behringer, and M. M. Matzuk Granulosa Cell-Specific Inactivation of Follistatin Causes Female Fertility Defects Mol. Endocrinol., April 1, 2004; 18(4): 953 - 967. [Abstract] [Full Text] [PDF]

				J. P. Hanrahan, S. M. Gregan, P. Mulsant, M. Mullen, G. H. Davis, R. Powell, and S. M. Galloway 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, April 1, 2004; 70(4): 900 - 909. [Abstract] [Full Text] [PDF]

				D. Mukhopadhyay, A. Asari, M. S. Rugg, A. J. Day, and C. Fulop Specificity of the Tumor Necrosis Factor-induced Protein 6-mediated Heavy Chain Transfer from Inter-{alpha}-trypsin Inhibitor to Hyaluronan: IMPLICATIONS FOR THE ASSEMBLY OF THE CUMULUS EXTRACELLULAR MATRIX J. Biol. Chem., March 19, 2004; 279(12): 11119 - 11128. [Abstract] [Full Text] [PDF]

				J. L. Juengel, N. L. Hudson, L. Whiting, and K. P. McNatty Effects of Immunization Against Bone Morphogenetic Protein 15 and Growth Differentiation Factor 9 on Ovulation Rate, Fertilization, and Pregnancy in Ewes Biol Reprod, March 1, 2004; 70(3): 557 - 561. [Abstract] [Full Text] [PDF]

				D. Schmidt, C. E. Ovitt, K. Anlag, S. Fehsenfeld, L. Gredsted, A.-C. Treier, and M. Treier The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance Development, February 15, 2004; 131(4): 933 - 942. [Abstract] [Full Text] [PDF]

				S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson The Bone Morphogenetic Protein System In Mammalian Reproduction Endocr. Rev., February 1, 2004; 25(1): 72 - 101. [Abstract] [Full Text] [PDF]