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Gonadal Development and Function
Jameson, J.L. | Weiss, J | Xu, E.Y.
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J. Larry Jameson, M.D., Ph.D.
Department of Medicine
M.D., Ph.D., University of North Carolina
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Dr. Jameson’s laboratory focuses on nuclear receptor action and diseases associated with mutations in nuclear receptors. These projects currently involve three main areas: 1) Estrogen receptor (ER) signaling through tethered, or non-classical, pathways. Using selective ER mutations that cannot bind directly to DNA, we have shown that many of the actions of ER in breast, uterus, and ovary are mediated through transcriptional pathways that do not involve direct binding to a canonical estrogen response element (ERE). Using targeted mutagenesis, we have developed a mouse model to examine these pathways in vivo. 2) Role of orphan nuclear receptors, such as SF-1 and DAX-1, in gonadal dysgenesis. SF-1 and DAX-1 are involved in the development and function of several endocrine glands, including the adrenal, the gonads, and the ventromedial hypothalamus. We are using combination of analyses of human mutations, gene knockouts, and promoter mutagenesis studies to further define the functional role of SF-1 and DAX-1 in gonadal development. 3) Role of Sox-3 in germ cell development. We showed that targeted mutagenesis of Sox3 prevents male germ cell differentiation. We are currently exploring the molecular pathways regulated by Sox3, including the possibility that it functions as a tumor suppressor gene in germ cell tumors.
Recent Publications:
Lim HJ, Park HY, Ko YG, Lee SH, Cho SY, Lee EJ, Jameson JL, Jang Y. Dominant negative insulin-like growth factor-1 receptor inhibits neointimal formation through suppression of vascular smooth muscle cell migration and proliferation, and induction of apoptosis. Biochem Biophys Res Commun. 2004 Dec 17;325(3):1106-14.
Baum AE, Solberg LC, Kopp P, Ahmadiyeh N, Churchill G, Takahashi JS, Jameson JL, Redei EE. Quantitative Trait Loci Associated with Elevated TSH in the Wistar-Kyoto Rat. Endocrinology. [Epub 2004 Oct 28].
Ishikawa T, Lee EJ, Jameson JL. Nonhomologous end-joining ligation transfers DNA regulatory elements between cointroduced plasmids. Mol Cell Biol. 2004 Oct;24(19):8323-31.
Jameson JL. Citation for the 2004 Sidney H. Ingbar Distinguished Service Award of The Endocrine Society to Dr. Margaret A. Shupnik. Endocr Rev. 2004 Aug;25(4):686-7.
Raverot G, Lejeune H, Kotlar T, Pugeat M, Jameson JL. X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility. J Clin Endocrinol Metab. 2004 Aug;89(8):4146-8.
Jameson JL. Molecular mechanisms of end-organ resistance. Growth Horm IGF Res. 2004 Jun;14 Suppl A:S45-50.
Gehm BD, Levenson AS, Liu H, Lee EJ, Amundsen BM, Cushman M, Jordan VC, Jameson JL. Estrogenic effects of resveratrol in breast cancer cells expressing mutant and wild-type estrogen receptors: role of AF-1 and AF-2. J Steroid Biochem Mol Biol. 2004 Mar;88(3):223-34.
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Jeffrey Weiss, Ph.D.
Center for Endocrinology,
Metabolism, and Molecular Medicine
Ph.D., University of Virginia
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The long-term goal of the laboratory is to understand the hormonal signals and cellular pathways through which the gonadotropin hormones, LH and FSH, are synthesized and secreted. In addition to the classic neuroendocrine and steroid signals, we have undertaken a detailed analysis of the autocrine and paracrine signals that specifically modulate pituitary FSH. These signals include activin, the potent and specific FSH stimulatory protein and follistatin, the activin binding protein. Recent work from the laboratory has confirmed the presence of activin and follistatin in the anterior pituitary and characterized an activin/follistatin paracrine loop that mediates the hypothalamic GnRH signal in a frequency-dependent manner. Studies are ongoing to identify the role of the GnRH/activin/follistatin interaction in the regulation of FSH required for follicular recruitment and maturation. Other projects in the laboratory include an analysis of the GnRH-and steroid-responsive regions of the follistatin promoter and studies to explore the regulation of the intracellular calcium channels during GnRH signalling. Previous studies in the laboratory identified the first known genetic mutation in a gonadotropin gene. This defect in the LHb gene formed the basis for hypergonadotropic hypogonadism in a family with a history of impaired fertility.
Recent Publications
Woodruff, TK, LM Besecke, N Groome, LB Draper, NB Schwartz, J Weiss. 1996. Inhibin A and inhibin B are inversely correlated to FSH yet are discordant during the follicular phase of the rat estrous cycle and inhibin A is expressed in a sexually dimorphic manner. Endocrinology 137:5463-5467.
Sundaresan, S, J Weiss, AC Bauer-Dantoin, JL Jameson. 1997. Expression of ryanodine receptors in the pituitary gland: Evidence for a role in GnRH signaling. Endocrinology 138:2056-2065.
Besecke, LM, MJ Guendner, PA Sluss, AG Polak, TK Woodruff, JL Jameson, AC Bauer-Dantoin, J Weiss. 1997. Pituitary follistatin regulates activin-mediated production of FSH during the rat estrous cycle. Endocrinology 138:2841-2848.
Draper, LB, MM Matzuk, VJ Roberts, E Cox, J Weiss, JP Mather, TK Woodruff. 1998. Identification of an inhibin receptor in gonadal tumors from inhibin a -subunit knockout mice. Journal of Biological Chemistry 273:398-403.
Wang, EY, LB Draper, E Lee, A Polak, P Sluss, J Weiss, TK Woodruff. 1999. Identification of Naturally Occurring Follistatin Complexes in Human Biological Fluids. Biology of Reproduction 60:8-13.
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Eugene Xu, Ph.D.
Department of Obstetrics and Gynecology
Ph.D., University of Chicago
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Germ cells are unique in that they are the only cell type in our bodies that is both totipotent and immortal. How germ cells in early embryos are formed and further developed into sperm and eggs remain one of the central questions in biology and a better understanding of this question could impact directly on our strategy in developing the diagnostic methods and treatment of diseases such as cancer, infertility and many other reproductive syndromes affecting men and women's health. The overall goal of my research program is to understand the genetic and developmental mechanisms of mammalian germline development, in particular how key events such as maintenance/differentiation of germline stem cells and entry into meiosis are regulated in mammals. The pathways that develop germ cells appear to be conserved broadly, at least in outline, in organisms as diverse as insects and mammals. We proposed that there exists conserved core machinery that regulates the germ cell development and we wish to define the components of this underlying machinery through a combined evolutionary, genomic and genetic approach.
Currently we are focusing on
- Dissection of meiotic regulatory machinery involving highly conserved meiotic regulator BOULE (meiosis, mouse genetics)
- Comparative genomic analysis of expression profile of germ cell development between fly and mouse (bioinformatics, genomics)
- Functional genomics approach to male and female contraception : Generation of mouse mutations disrupting conserved reproductive regulators from mouse ES genetrap lines (mouse genetics, development)
- Role of conserved germline stem cell factors Pumilio 1 and Pumilio 2. (stem cell, development)
- Use of mouse and human ES cells as an invitro system for applications in reproductive biology research (cell biology and cancer)
Recent Publications:
Xu, E. Y., D. Lee, A. Klebes, P. J. Turek, T. Kornberg and R. Reijo Pera (2003) Human BOULE rescues the meiotic defects in infertile flies Human Molecular Genetics. Vol 12(2):169-175.
Wu, C.-I. and Xu, E. Y. (2003) Sexual antagonism and X inactivation- the SAXI hypothesis. Trends in Genetics 19(5): 243-7
Xu, E. Y., F. Moore, R. Reijo Pera (2001) A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans. PNAS Vol 98:7414-7419
C. Marc Luetjens, Xu, E. Y., Renee A. Reijo Pera, Axel Kamischke, Eberhard Nieschlag, Jšrg Gromoll (2004) Association of meiotic arrest in infertile men and lack of BOULE protein expression. J. Clinical Endocrinology and Metabolism 89(4):1926-33
Y.-M. Kuo, J. Duncan, S. Westaway,H. Yang, G. Nune, Xu, E. Y., S. Hayflick, and J. Gitschier (2004) Deficiency in pantothenate kinase 2 in a mouse model for Hallervorden-Spatz Syndrome leads to retinal degeneration and azoospermia Human Molecular Genetics 14(1):49-57
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