1 year ago

2004 Scientific Report

External Collaborators

External Collaborators Ermanno Gherardi, University of Cambridge, United Kingdom Steve Kliewer, University of Texas Southwestern Medical Center, Dallas Mill Lambert and Tim Willson, GlaxoSmithKline Inc., Research Triangle Park, North Carolina Donald MacDonnell, Duke University, Durham, North Carolina Stoney Simmons, National Institutes of Health, Bethesda, Maryland Brad Thompson, University of Texas Medical Branch at Galveston Ming-Jer Tsai, Baylor College of Medicine, Houston, Texas Scott Thacher, Orphagen Pharmaceuticals, San Diego, California Recent Publications Agostini Maura, Mark Gurnell, David B. Savage, Emily M. Wood, Aaron G. Smith, Odelia Rajanayagam, Keith T. Garnes, Sidney H. Levinson, H. Eric Xu, John W.R. Schwabe, Timothy M. Willson, Stephen O’Rahilly, and V. Krishna Chatterjee. 2004. Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor γ. Endocrinology 145(4): 1527–1538. Stanley, T.B., L.M. Leesnitzer, V.G. Montana, C.M. Galardi, M.H. Lambert, H.E. Xu, L.B. Moore, S.G. Blanchard, and J.B. Stimmel. 2003. Subtype-specific effects of peroxisome proliferator–activated receptor ligands on co-repressor affinity. Biochemistry 42: 9278–9287. Li, Yong, Millard H. Lambert, and H. Eric Xu. 2003. Activation of nuclear receptors: a perspective from structural genomics. Structure 11(7): 741–746. Sznaidman, Marcos L., Curt D. Haffner, Patrick R. Maloney, Adam Fivush, Esther Chao, Donna Goreham, Michael L. Sierra, Christelle LeGrumelec, H. Eric Xu, Valerie G. Montana, Millard H. Lambert, Timothy M. Willson, et al. 2003. Novel selective small molecule agonists for peroxisome proliferator–activated receptor δ (PPARδ)—synthesis and biological activity. Bioorganic & Medicinal Chemistry Letters 13(9): 1517–1521. Xu, H.E., and M.H. Lambert. 2003. Structural insights into regulation of nuclear receptors by ligands. NURSA e-journal 1(1): ID# 3.06132003.06132001. Xu, H.E., and M.H. Lambert. 2003. Structural mechanisms of ligand-mediated signaling by nuclear receptors. In Handbook of Cell Signaling, R.A. Bradshaw and E.A. Dennis, eds. Vol. 3, Chap. 272. San Diego: Academic Press. From left to right: Daugherty, Kretschman, Kovach, Suino, Reynolds, Tolbert, Xu, Li 64

Laboratory of Mammalian Developmental Genetics Nian Zhang, Ph.D. Dr. Zhang received his M.S. in entomology from Southwest Agricultural University, People’s Republic of China, in 1985 and his Ph.D. in molecular biology from the University of Edinburgh, Scotland, in 1992. From 1992 to 1996, he was a postdoctoral fellow at the Roche Institute of Molecular Biology. He next served as a postdoctoral fellow (1996) and a Research Associate (1997–1999) in the laboratory of Tom Gridley in mammalian developmental genetics at the Jackson Laboratory, Bar Harbor, Maine. Dr. Zhang joined VARI as a Scientific Investigator in December 1999. Staff Jun Chen, M.D., Ph.D. Lan Wang, Ph.D. Liang Kang Laboratory Members Visiting scientist Dong Kong, Ph.D. Research Interests We are interested in understanding the cellular and molecular mechanisms underlying pattern formation during embryonic development. We previously cloned and targeted the mouse Lunatic fringe (Lfng) gene, which plays an important role in embryo segmentation. Mice homozygous for the Lfng mutation suffer from severe malformation of their axial skeleton as a result of irregular somite formation during embryonic development. Lfng encodes a secreted signaling molecule essential for regulating the Notch signaling pathway in mice. We showed that Lfng expression was in response to a biological clock that oscillated once during the formation of each segment, and the failure of the Lfng mutants in responding to this clock resulted in the abnormal segmentation phenotype. We want to understand how the rhythmic expression of Lfng is controlled. Our recent studies indicate that the cyclic expression of Lfng is controlled by a negative feedback loop. The signals transmitted through the loop are mediated by the components in the Notch signaling pathway. We found that that there is a binary switch that determines the “on” and “off” states of Lfng transcription. When Lfng is on, it modifies the Notch receptors, therefore activating the downstream effecter Hes7, a transcription repressor. We found that Hes7 can directly bind to the 5′ regulatory region of the Lfng gene and switch off the transcription of Lfng. When Lfng is down-regulated, it results in down-regulation of Hes7 and thus relieves the transcriptional repression of Hes7 on Lfng. We have also demonstrated that the 3′ untranslated region (UTR) is important for the rapid degradation of Lfng mRNA, which ensures accurate oscillation. Germ cell development The second focus of our laboratory is on germ cell development—particularly the mechanisms that govern germ cell migration, survival, spermatogonial stem cell renewal, and differentiation—and the implications for human disease. It is unclear how spermatogonial stem cells are regenerated during the entire reproductive life in mammals. Previous studies on the nematode Caenorhabditis elegans have shown that the Notch/lin12-mediated signal transduction pathway is important if germ cells are to remain in an undifferentiated state. Mutations that compromise this pathway force germ cells to enter meiosis earlier than normal. A constitutively activated signal prevents germ cells from entering meiosis, resulting in overproliferation of germ cells, a phenotype called “germ cell tumor.” Given the fact that some members in the Notch signaling pathway are expressed in the testis, we speculate that Notch signaling may play a similar role in spermatogonial differentiation in mammals. We will further examine the role Notch signaling may play during spermatogenesis using transgenic animals and conditional gene targeting. We are also studying spontaneous mutations that cause sterility. In mice, primordial germ cells (PGCs) are differentiated from the epiblasts during an early embryonic stage. After their formation, they migrate through the dorsal mesen- 65

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