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2002 Scientific Report

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Laboratory of

Laboratory of 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. Laboratory Members Staff Jun Chen, M.D., Ph.D. Jihong Ma, Ph.D. Lan Wang, Ph.D. Liang Kang Research Projects W e 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 in their axial skeletons 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. Using transgenic animals, we are analyzing regulatory elements that control Lfng expression, and we are also isolating genes that regulate Lfng expression. In addition, we are identifying proteins that interact with Lfng during embryo segmentation. Another approach that we are taking to understand somitogenesis is to examine a spontaneous mutant with a phenotype similar to that of the Lfng mutant. We plan to clone this mutation positionally and test if this mutation interacts with Lfng and other mutations that affect somitogenesis. The second focus of our laboratory is germ cell development, particularly the mechanisms that govern germ cell migration, survival, spermatogonial stem cell renewal and differentiation, and their 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 for germ cells 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 a spontaneous mutation that causes sterility. Preliminary data suggest that this mutation arrests the development of spermatogenic cells at meiosis II. We are interested in identifying the gene that is disrupted by this mutation and understanding the role that this gene plays in meiosis. 61

External Collaborators Xiang Gao, Center of Model Animal Genetics, Nanjing University, People’s Republic of China Douglas L. Pittman, Medical College of Ohio, Toledo From left to right: Chen, Kang, Wang, Zhang 62

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