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The Bone Morphogenetic Protein System In Mammalian Reproduction

Department of Reproductive Medicine, University of California San Diego, School of Medicine, La Jolla, California 92093-0633

Correspondence: Address all correspondence and requests for reprints to: Shunichi Shimasaki, Ph.D., Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0633. E-mail: sshimasaki{at}ucsd.edu

Using molecular, cellular, and genetic approaches, recent studies examining the role of the bone morphogenetic protein (BMP) family of growth factors in the reproductive system have led to significant breakthroughs in our understanding of mammalian reproduction and fertility. Gene expression studies have revealed that key components of the BMP system (ligands, receptors, signaling molecules, and binding proteins) exhibit coordinated spatial and temporal expression patterns in fundamental cell types throughout the reproductive system. Availability of recombinant BMPs has enabled functional studies that have demonstrated important biological activities of BMPs in controlling cellular proliferation, differentiation, and apoptosis in reproductive tissues. The physiological importance of the BMP system for mammalian reproduction has been further highlighted by the elucidation of the aberrant reproductive phenotypes of animals with naturally occurring mutations or targeted deletions of certain BMP family genes. Collectively, these studies have established the concept that the BMP system plays a crucial role in fertility in female and male mammals. The purpose of this article is to review the evidence underpinning the importance of the BMP system in mammalian reproduction.

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				O. Hashimoto, R. K. Moore, and S. Shimasaki Posttranslational processing of mouse and human BMP-15: Potential implication in the determination of ovulation quota PNAS, April 12, 2005; 102(15): 5426 - 5431. [Abstract] [Full Text] [PDF]

				K. P McNatty, J. L Juengel, K. L Reader, S. Lun, S. Myllymaa, S. B Lawrence, A. Western, M. F Meerasahib, D. G Mottershead, N. P Groome, et al. Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function Reproduction, April 1, 2005; 129(4): 473 - 480. [Abstract] [Full Text] [PDF]

				K. P McNatty, J. L Juengel, K. L Reader, S. Lun, S. Myllymaa, S. B Lawrence, A. Western, M. F Meerasahib, D. G Mottershead, N. P Groome, et al. Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants Reproduction, April 1, 2005; 129(4): 481 - 487. [Abstract] [Full Text] [PDF]

				B. D. Cherrington, T. A. Farmerie, C. A. Lents, J. D. Cantlon, M. S. Roberson, and C. M. Clay Activin Responsiveness of the Murine Gonadotropin-Releasing Hormone Receptor Gene Is Mediated by a Composite Enhancer Containing Spatially Distinct Regulatory Elements Mol. Endocrinol., April 1, 2005; 19(4): 898 - 912. [Abstract] [Full Text] [PDF]

				C. Glister, S. L. Richards, and P. G. Knight 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, April 1, 2005; 146(4): 1883 - 1892. [Abstract] [Full Text] [PDF]

				Y. Park, E. T. Maizels, Z. J. Feiger, H. Alam, C. A. Peters, T. K. Woodruff, T. G. Unterman, E. J. Lee, J. L. Jameson, and M. Hunzicker-Dunn Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad J. Biol. Chem., March 11, 2005; 280(10): 9135 - 9148. [Abstract] [Full Text] [PDF]

				J.L. Juengel and K.P. McNatty The role of proteins of the transforming growth factor-{beta} superfamily in the intraovarian regulation of follicular development Hum. Reprod. Update, March 1, 2005; 11(2): 144 - 161. [Abstract] [Full Text] [PDF]

				F. H. Thomas, J.-F. Ethier, S. Shimasaki, and B. C. Vanderhyden Follicle-Stimulating Hormone Regulates Oocyte Growth by Modulation of Expression of Oocyte and Granulosa Cell Factors Endocrinology, February 1, 2005; 146(2): 941 - 949. [Abstract] [Full Text] [PDF]

				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]

				M. Takeda, F. Otsuka, K. Nakamura, K. Inagaki, J. Suzuki, D. Miura, H. Fujio, H. Matsubara, H. Date, T. Ohe, et al. Characterization of the Bone Morphogenetic Protein (BMP) System in Human Pulmonary Arterial Smooth Muscle Cells Isolated from a Sporadic Case of Primary Pulmonary Hypertension: Roles of BMP Type IB Receptor (Activin Receptor-Like Kinase-6) in the Mitotic Action Endocrinology, September 1, 2004; 145(9): 4344 - 4354. [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. A. Pangas, C. J. Jorgez, and M. M. Matzuk Growth Differentiation Factor 9 Regulates Expression of the Bone Morphogenetic Protein Antagonist Gremlin J. Biol. Chem., July 30, 2004; 279(31): 32281 - 32286. [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]