2001 - Center for Advanced Biotechnology and Medicine - Rutgers ...

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__________________________________________________________________________________ Center for Advanced Biotechnology and Medicine James H. Millonig cycle. Preliminary data suggests that the last could be true, indicating that the roof plate coordinates the withdrawal of cells from the cell cycle (Tanya Borusk, unpublished results). Splotch (Sp), another mouse mutant, exhibits a similar cell cycle withdrawal phenotype, providing us with two mutations that together should lead to insights into the molecular mechanisms that control dorsal neuronal generation. Another spontaneous mouse mutation, vacuolated lens (vl), appears to have the opposite phenotype to dr, too much roof plate. Vl/vl embryos have an expanded dorsal midline and exhibit phenotypes consistent with too much roof plate, such as an increase in the number of dorsal neurons and overgrowth of the dorsal vertebrae that lie above the roof plate. In dr, this part of the vertebrae is missing. Vl maps near the dr locus but sequencing of Lmx1a from vl/vl embryos indicates that Lmx1a is not responsible for the mutation (Jigar Desai, unpublished results). We are now in the process of positionally cloning the locus. We have also been focusing on identifying genes that are downstream of roof plate signaling. To this end, we have identified transcription factors that are expressed in nested domains in the developing cerebellum that appear to be restricted to particular cellular populations (Max Tischfield, unpublished results). Phenotypic analysis of dr embryos and in vitro explants are being used to determine if roof plate signaling is necessary and sufficient for the expression of these dorsal markers. The function of these genes is being tested through a combination of mouse genetics and the forced misexpression in the cerebellum during chick embryogenesis. Through these different approaches the pathways involved in dorsal CNS development will be ascertained. Publications: Millonig, J.H., Millen, K.J and Hatten, M.E. (2000) The Mouse Dreher gene (Lmx1a) Controls Formation of the Roof Plate Formation in Vertebrate CNS. Nature. 403:764-768. 18
Michael M. Shen, Ph.D. Resident Faculty Member, CABM; Associate Professor, UMDNJ-Robert Wood Johnson Medical School, Department of Pediatrics Mammalian Embryogenesis Laboratory Dr. Michael Shen completed his doctoral work in genetics under Dr. Jonathan Hodgkin at the MRC laboratory of Molecular Biology in Cambridge, England. He then performed postdoctoral work at Harvard Medical School under Dr. Philip Leder before joining CABM in 1994. He is a former recipient of a Leukemia Society of America Special Fellowship, a Howard Hughes Medical Institute Post-doctoral Fellowship, a Jane Coffin Childs Post-doctoral Fellowship, and a National Science Foundation Graduate Fellowship. Dr. Shen is a member of the NIH Study Section on Cell Development and Function and of the National Cancer Institute Steering Committee for the Mouse Models of Human Cancer Consortium. The research in our laboratory is directed towards understanding the molecular mechanisms involved in (i) formation of the embryonic anterior-posterior and left-right axes in the mouse embryo, (ii) signal transduction by EGF-CFC proteins and the TGF-beta-related factor Nodal, and (iii) prostate development and carcinogenesis. To address the first two areas, we are pursuing studies of the recently identified EGF-CFC gene family, whose members encode novel extracellular proteins. We have used gene targeting approaches in mice to demonstrate that EGF-CFC genes play essential roles in embryonic axis formation, namely that Cripto is required for correct orientation of the anterior-posterior (A-P) axis, while Cryptic is necessary for determination of the left-right (L-R) axis. Thus, targeted disruption for Cripto results in a 90 degree mis-orientation of the A-P axis, indicating that Cripto is essential for an axial rotation that converts a proximal-distal asymmetry into an orthogonal A- P axis during pre-gastrulation stages. In contrast, null mutation for Cryptic results in L-R laterality defects, including randomized abdominal situs, pulmonary right isomerism, and severe cardiac defects, as well as lack of expression of regulatory genes in the L-R pathway, suggesting that Cryptic is essential for a key step in L-R axis specification. Our results also support an interaction of EGF-CFC proteins with the TGF-beta-related factor Nodal and with activin receptors, which we are currently examining using biochemical and cell culture approaches. In another major area of interest, we are investigating prostate development and cancer (in collaboration with Dr. Cory Abate-Shen's lab). We are focusing on the role of the Nkx3.1 homeobox gene, which displays restricted expression in the embryonic and adult mouse prostate. We have demonstrated that homozygous Nkx3.1-/- mice created by gene targeting display progressive defects in prostate histology with advancing age, resulting in epithelial hyperplasia and dysplasia. These lesions in aged mutant mice resemble human prostatic intraepithelial neoplasia (PIN), which is believed to represent the precursor to prostate carcinoma. These observations are noteworthy given the mapping of human NKX3.1 to the minimal deleted interval of chromosome 8p21, which is lost as an early and frequent event in human prostate cancer. Our findings show that Nkx3.1 plays a critical role in the normal morphogenesis and function of the prostate, and suggest that it may represent a prostate-specific tumor suppressor gene. __________________________________________________________________________________ Center for Advanced Biotechnology and Medicine 19
Page 1 and 2: C A B M Center for Advanced Biotech
Page 3 and 4: Director’s Overview The community
Page 5 and 6: Research Programs and Laboratories
Page 7 and 8: Cory Abate-Shen, Ph.D. Resident Fac
Page 9 and 10: Isaac Edery, Ph.D. Resident Faculty
Page 11 and 12: Céline Gélinas, Ph.D. Resident Fa
Page 13 and 14: Fang Liu, Ph.D. Resident Faculty Me
Page 15 and 16: Peter Lobel, Ph.D. Resident Faculty
Page 17: James H. Millonig, Ph.D. Resident F
Page 21 and 22: Eileen White, Ph.D. Associate Inves
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Page 31 and 32: Gaetano Montelione, Ph.D. Resident
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Page 39 and 40: Arnold B. Rabson, M.D. Resident Fac
Page 41 and 42: Aaron J. Shatkin, Ph.D. Director, C
Page 43 and 44: Education, Training & Technology Tr
Page 45 and 46: January 24 James Manley, Biological
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