Department of Reproductive Medicine

Shunichi Shimasaki

Shunichi Shimasaki
Professor of Reproductive Medicine
Division of Reproductive Endocrinology

Administrative Office:
9500 Gilman Drive
Biomedical Science Building 5046B
La Jolla, CA. 92093
Telephone:858-822-1414
Fax: (858) 822-1482
Email:sshimasaki@ucsd.edu


Education

Ph.D. in Medical Science
Kawasaki Medical School, Okayama, Japan, 1985

M.Sc. in Chemistry
Hiroshima University, Hiroshima, Japan, 1977

Teaching

Molecular Principles of Growth Factor Biology

Service

Director, Molecular Biology Teaching Core Laboratory of Women’s Reproductive Health Research Career Development Center

Member, Specialized Cooperative Centers Program in Reproduction Research (NIH)

Training Grant Faculty, NIH Training Program in Reproductive Sciences

Member, Academic Senate

Member, Biomedical Sciences Graduate Program

Research Field

Molecular and Cellular Biology of Ovarian Function

Current Research Focus

Our laboratory is interested in the role of growth/differentiation factors in regulating the mammalian reproductive system; specifically how they control ovarian follicle development and ovulation. The precise physiological control of ovarian folliculogenesis is critical for the determination of ovulation rate, thus female fertility. Alterations in this process are known to cause ovarian dysfunction and infertility.

A major emphasis of our current research program focuses on the role of TGF-ß superfamily members in regulating granulosa cell proliferation and cytodifferentiation, oocyte development and oocyte-somatic cell communication. In the course of this research we have discovered the presence of a functional bone morphogenetic protein (BMP) system, replete with BMP ligands, receptors and novel biological functions in the mammalian ovary. It has now become clear that the BMP system plays an essential role in the regulation of ovarian function, evidenced by the ability of BMPs to control ovulation rate and fertility. These properties of the BMP system provide the potential for a unique approach to the development of pharmacological regimens for regulating ovarian function, including: i) novel fertility treatments aimed at enhancing fertility at the level of early follicular growth, ii) the development of new non-steroidal contraceptives and iii) treatments designed to delay of the depletion of the ovarian reserve of follicles, thus the delay of the onset of menopause. We believe that a better understanding of the spatiotemporal gene expression and biological actions of the BMP system in the ovary may help clinicians find a role for the BMPs in the diagnosis and treatment of reproductive disorders that affect human fertility.

Our research protocols utilize molecular, cellular and biochemical approaches as well as genetics to study how specific growth factors regulate granulosa cell function, to identify the spatiotemporal expression patterns of ovarian genes throughout the reproductive cycle, to elucidate the signal transduction pathways of growth factors in granulosa cells and to study communication pathways between oocytes and somatic cells which are important for normal ovarian function.

Recent Selected Publications

Hashimoto, O., Nakamura, T., Shoji, H., Shimasaki, S., Hayashi, Y., Sugino, H. A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate. J. Biol. Chem. 272:13835-13842, 1997.

Iemura, S., Yamamoto, T.S., Takagi, C., Hideho, U., Natsume, T., Shimasaki, S., Sugino, H., Ueno, N. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc. Natl. Acad. Sci. U.S.A. 95:9337-9342, 1998.

Shimasaki, S., Zachow, R.J., Li, D., Kim,H., Iemura, S., Ueno, N., Sampath, K., Chang, R.J., Erickson, G.F. A Functional Bone Morphogenetic Protein System in the Ovary. Proc. Natl. Acad. Sci. U.S.A. 96:7282-7287, 1999.

Erickson G.F., Shimasaki, S. The role of the oocyte in folliculogenesis (Review article). Trends. Endocrinol. Metab. 11:193-198, 2000.

Yamamoto T.S., Iemura S.-I., Takagi C., Shimasaki, S., Ueno N. Characterization of follistatin isoforms in early Xenopus embryogenesis. Int. J. Dev. Biol. 44:341-348, 2000.

Hashimoto, O., Kawasaki, N., Tsuchida, K., Shimasaki, S., Hayakawa, T., Sugino, H. Difference between follistatin isoforms in the inhibition of activin signalling. Activin neutralizing activity of follistatin isoforms is dependent on their affinity for activin. Cell Signal 12:565-571, 2000.

Otsuka, F., Yao, Z., Lee, T.-H., Yamamoto, S., Erickson, G.F., Shimasaki, S. Bone morphogenetic protein-15: Identification of target cells and biological functions. J. Biol. Chem. 275:39523-39528, 2000.

Otsuka, F., Yamamoto, S., Erickson, G.F., Shimasaki, S. Bone morphogenetic protein-15 inhibits follicle-stimulating hormone (FSH) action by suppressing FSH receptor expression. J. Biol. Chem. 276:11387-11392, 2001.

Otsuka, F., Moore, R.K., Shimasaki, S. Biological function and cellular mechanism of bone morphogenetic protein-6 in the ovary. J. Biol. Chem. 276:32889-32895, 2001.

Lee,W-S., Otsuka, F., Moore, R.K., Shimasaki, S. Effect of bone morphogenetic protein-7 on folliculogenesis and ovulation in the rat. Biol. Reprod. 65: 994-999, 2001.

Erickson, G.F., Shimasaki, S. Physiology of folliculogenesis: the role of the oocyte (Review article). Fertil. Steril. 76:943-949, 2001.

Moore, R.K., Otsuka, F., Shimasaki, S. Role of ERK1/2 in the differential synthesis of progesterone and estradiol by granulosa cells. Biochem. Biophys. Res. Commun. 289:796-800, 2001.

Otsuka,F., Moore, R.K., Iemura, S.-I., Ueno, N., Shimasaki, S. Follistatin Inhibits the function of the oocyte-derived factor BMP-15. Biochem. Biophys. Res. Commun. 289:961-966, 2001.

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. U.S.A. 99:8060-8065, 2002.

Nakatani, M., Yamakawa, N., Matsuzaki, T., Shimasaki, S., Sugino, H., Tsuchida, K. Genomic organization and promoter analysis of mouse follistatin-related gene (FLRG). Mol. Cell Endocrinol. 189:117-1123, 2002.

Teixeira Filho, F.L., Baracat, E.C., Lee, T.H., Suh, C.S., Matsui, M., Change, R.J., Shimasaki, S., Erickson, G.F. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 87:1337-1344, 2002.

Otsuka F., Shimasaki, S. A novel function of bone morphogenetic protein-15 in the pituitary: Selective synthesis and secretion of FSH by gonadotropes. Endocrinology 143:4938-4941, 2002.

Moore, R.K., Otsuka, F., Shimasaki, S. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J. Biol. Chem. 278:304-310, 2003.

Liao, W.X., Moore, R.K., Otsuka, F., Shimasaki, S. Effect of heterodimerization on processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9: Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. J. Biol. Chem. 278:3713-3719, 2003.

Erickson, G.F, Shimasaki, S. The spatiotemporal expression pattern of the bone morphogenetic protein family in rat ovary cell types during the estrous cycle. Reprod. Biol. Endocrinol.1:9, 2003.

Shimasaki, S., Moore, R.K., Otsuka, F., Erickson, G.F. The bone morphogenetic protein system in mammalian reproduction (Review article). Endocr. Rev. 25:72-101, 2004 (cover article).

Liao, W.X., Moore, R.K., Shimasaki, S. Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors BMP-15 and GDF-9. J. Biol. Chem. 279:17391-17396, 2004.

Matsui, M., Sonntag, B., Soo Hwang, S., Byerly, T., Hourvitz, A., Adashi, E.Y., Shimasaki, S., Erickson, G.F. Pregnancy-Associated Plasma Protein-A (PAPP-A) Production in Rat Granulosa Cells: Stimulation by Follicle Stimulating Hormone and Inhibition by the Oocyte-Derived Bone Morphogenetic Protein-15. Endocrinology 145: 3686-3695, 2004.

Moore, R.K., Erickson, G.F., Shimasaki, S. Are BMP-15 and GDF-9 primary determinants of ovulation quota in mammals? Trends Endocrinol Metab 15:356-361, 2004 (cover article).

Thomas, F.H., Ethier, J.F., Shimasaki, S., Vanderhyden, B.C. Follicle-Stimulating Hormone regulates oocyte growth by modulation of expression of oocyte and granulosa cell factor. Endocrinology 146:941-949, 2005.

Hashimoto, O., Moore, R.K., Shimasaki, S. Post-translational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota Proc. Natl. Acad. Sci. U.S.A. 102:5426-5431, 2005.

Otsuka, F., Moore, R.K., Wang, X., Sharma, S., Miyoshi, T., Shimasaki, S. Essential role of the oocyte in estrogen amplification of follicle-stimulating hormone signaling in granulosa cells. Endocrinology 146: 3362-3367, 2005.

Clelland E, Kohli G, Campbell RK, Sharma S, Shimasaki S, Peng C. Bone morphogenetic protein-15 in the zebrafish ovary: Complementary deoxyribonucleic acid cloning, genomic organization, tissue distribution and role in oocyte maturation. Endocrinology 147:201-209, 2006.

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. Proc. Natl. Acad. Sci. U.S.A. 103:10678-10683, 2006.

Lerch, T.F., Shimasaki, S., Woodruff, T.K., Jardetzky, T.S. Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions. J. Biol. Chem. 282:15930-15939, 2007.

Sugiura, K., Su, Y-Q., Diaz, F.J., Pangas, S.A., Sharma, S., Wigglesworth, K., O'Brien, M.J., Matzuk, M.M., Shimasaki, S., Eppig, J.J.Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development 134:2593-2603, 2007.

McMahon, HE., Sharma, S., Shimasaki, S. Phosphorylation of bone morphogenetic protein-15 and growth and differentiation factor-9 plays a critical role in determining agonistic or antagonistic functions. Endocrinology 149:812-817, 2008.

Saito S., Yano, K., Sharma, S., McMahon, HE., Shimasaki, S. Characterization of the posttranslational modification of recombinant human BMP-15 mature protein. Protein Sci. 17:362-370, 2008.

Wachs, D.S., Coffler, M.S., Malcom, P.J., Shimasaki, S., Chang, R.J. Increased FSH-stimulated Androgen Release in Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 93:1827-1833, 2008.

McMahon, H.E., Hashimoto, O., Mellon, P.L., Shimasaki, S. Oocyte-specific over-expression of mouse BMP-15 leads to accelerated folliculogenesis and an early onset of acyclicity in transgenic mice. Endocrinology 149:2807-2815, 2008.

 

Earlier Major Accomplishment

Discovery and Structural Characterization of Novel Regulatory Polypeptides including

Activin (Nature 321:779-792, 1986)
Follistatin (Proc. Natl. Acad. Sci. U.S.A. 84:8282-8286, 1987)
Nicotinic acetylcholine receptor (Neuron 1:241-248, 1988)
Kainate receptor (Nature 342:684-689, 1989)
Insulin-like growth factor binding protein-3 (Endocrinology 125:912-916, 1989)
Insulin-like growth factor binding protein-4 (Biochem. Biophys. Res. Commun. 165:189-195, 1989)
Transcription factor IIE-alpha (Nature 354:398-401, 1991)
Transcription factor IIE-beta (Nature 354:401-404, 1991)
Insulin-like growth factor binding protein-5 (J. Biol. Chem. 266:10646-10653, 1991)
Insulin-like growth factor binding protein-6 (Mol. Endocrinol. 5:938-948, 1991)
Dipeptidyl aminopeptidase (Proc. Natl. Acad. Sci. U.S.A. 89:197-201, 1992)

Molecular Cloning of Novel cDNAs and Genes including

Follicle-stimulating hormone ß subunit (Proc. Natl. Acad. Sci. U.S.A. 83:6618-6621, 1986)
Inhibin/Activin alpha, ßA and ßB subunit (Mol. Endocrinol. 1:388-396, 1987)
Basic fibroblast growth factor (Biochem. Biophys. Res. Commun. 157:256-263, 1988)
Follistatin (Proc. Natl. Acad. Sci. U.S.A. 85: 4218-4222, 1988)
Insulin-like growth factor binding protein-3 (J. Biol. Chem. 265:2198-2202, 1990)
Insulin-like growth factor binding protein-4 (Mol. Endocrinol. 4:1451-1458, 1990)
Insulin-like growth factor binding protein-5 (J. Biol. Chem. 266:10646-10653, 1991)
Insulin-like growth factor binding protein-6 (Mol. Endocrinol. 5:938-948, 1991)

Laboratory Personnel

Miao Chang, Ph.D. Postdoctoral Fellow
Yvonne Hoang, Ph.D. Postdoctoral Fellow
Kirsten McTavish , Ph.D. Postdoctoral Fellow
Fabian Nonis , Ph.D. Postdoctoral Fellow
Heidi Cook-Anderson , Ph.D. Postdoctoral Fellow
Lishuang (Lily) Xu Staff Research Assoc.

 

Administrative Assistant

Andi Hartgrove

email: ahartgrove@ucsd.edu

Phone: (858) 534-8930

 

Faculty