David Stein

David Stein

	Associate Professor Ph.D. Stanford University d.stein@mail.utexas.edu Office 637 PAT (512) 232-3378 Stein Lab home page


Our laboratory uses the fruit fly Drosophila as a model system to study the mechanisms regulating embryonic development and to investigate the genetic networks that control growth and proliferation. The Drosophila system enables us to utilize sophisticated genetic techniques that cannot be used in studies of human beings or other vertebrate model organisms. Insights derived from studies of particular proteins in model animal systems such as Drosophila can often be extended to processes occurring in human beings that involve the same or similar proteins. The main project in the lab investigates how a complex multicellular organism develops from a seemingly simple single cell, the fertilized Drosophila egg. Specifically, we are studying how dorsal-ventral polarity is established during embryogenesis. The polarity of the embryonic dorsal-ventral axis is defined by a ventrally-produced extracellular ligand which binds to and activates Toll, a receptor protein present in the membrane of the embryo. Formation of this ligand is mediated by a cascade of serine proteolytic activity that occurs in the perivitelline fluid between the embryonic membrane and the inner layer of the egg shell. We are investigating the mechanism by which this serine proteolytic cascade is activated in a spatially-specific way. We have recently cloned the pipe locus, which regulates this process and found that it exhibits ventrally-restricted expression in the ovarian follicle in which the egg develops. Moreover, pipe encodes an enzyme that mediates oligosaccharide sulfation. Our continuing studies will seek to elucidate the spatial restriction of pipe expression and understand how spatially-regulated carbohydrate modification mediated by the pipe gene product leads to ventral formation of the Toll ligand and hence correct embryonic polarity. In a second project, we are using Drosophila to understand the function of the oncogene, c-myc. It has been estimated that alterations in the c-myc oncogene are associated with approximately 70,000 U.S. cancer deaths per year, representing one seventh of the annual cancer mortality. However, the mechanism by which changes in c-myc activity and/or expression lead to cancer is poorly understood, as is its normal function in the life of the cell. We and our collaborators isolated the Drosophila c-myc homologue and demonstrated that it corresponded to a previously identified genetic locus, designated diminutive (dm). Ongoing studies in the lab are investigating the normal function of dm in the biology of the fly, using newly generated lethal alleles of dm. Further, we are carrying out genetic screens to identify mutations that modify dm function or expression. We anticipate that Drosophila genes found to interact with dm will have human homologues that may serve as targets for therapeutic intervention of myc-related cancer.

Selected Publications Roth, S., Stein, D., and NŸsslein-Volhard, C. A Gradient of nuclear localization of the Dorsal protein determines pattern in the Drosophila embryo. Cell 59: 1189-1202. (1989). Stein, D., Roth, S., Vogelsang, L., and NŸsslein-Volhard, C. The polarity of the dorso-ventral axis in the Drosophila embryo is defined by an extracellular signal. Cell 65, 725-735. (1991). Stein, D., and Stevens, L.M. Establishment of dorsal-ventral and terminal pattern in the Drosophila embryo. Curr. Opin. Gen. Dev.1: 247-254. (1991). Stein, D., and NŸsslein-Volhard, C. Multiple extracellular activities in Drosophila egg perivitelline fluid are required for establishment of embryonic dorsal-ventral polarity. Cell: 68, 429-440. (1992). Stein, D. The link between ovary and embryo. Current Biology 5, 1360-1363. (1995). Bergmann, A., Stein, D., Geisler, R., Hagenmeier, S., Schmid, B., Fernandez, N., Schnell, B., and NŸsslein-Volhard, C. A gradient of cytoplasmic Cactus degradation establishes the nuclear localization gradient of the Dorsal morphogen in Drosophila.Mech. Dev. 60, 109-123. (1996). Schreiber-Agus, N., D. Stein., Chen, K., Goltz, J.S., Stevens, L., and DePinho, R.A. Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. PNAS 94, 1235-1240. (1997). Stein, D., Goltz. J, S., Jurcsak, J, and Stevens, L. The Dorsal-related immunity factor (Dif) can define the dorsal-ventral axis of polarity in the Drosophila embryo. Development. 125, 2159-2169. (1998). Briggs, L. J., Stein, D., Goltz, J., Corrigan, V.C., Efthymiadis, A., Huebner, S., and Jans, D.A. The cAMP-dependent protein kinase site (Ser312) enhances Dorsal nuclear import through facilitting nuclear localization seqeunce/Importin interaction.J.Biol. Chem. 273, 22745-22752.(1998). Galbiati, F., Volonte, D., Goltz, J.S., Steele, Z., Sen, J., Jurcsak, J., Stein, D., Stevens, L., Lisanti, M.P. Identification, sequence and developmental expression of invertebrate flotillins from Drosophila melanogaster. Gene 210, 229-237. (1998). Sen, J., Goltz, J.A., Stevens, L., and Stein, D. Spatially-restricted expression of pipe in the Drosophila egg chamber defines embryonic dorsal-ventral polarity. Cell 95, 471-481. (1998). Han, D. D., Stein, D., and Stevens, L.M. Investigating the function of follicular subpopulations during Drosophila oogenesis through hormone-dependent enhancer-targeted cell ablation. Development 127, 573-583. (2000). Jordan, K.C., Clegg, N.J., Blasi, J.A., Morimoto, A.M., Sen, J., Stein, D., McNeill, H., Deng, W.-M., Tworoger, M. & Ruohola-Baker, H. The homeobox gene mirror links EGF signaling to embryonic dorso-ventral axis formation through Notch activation. Nature Genetics, 24, 4239-433. (2000) Fernandez, R., Takahashi, F., Liu, Z., Steward, R., Stein, D., and Stanley, E.R. The Drosophila shark tyrosine kinase is required for embryonic dorsal closure. Genes and Development 14, 604-614. (2000). Sen, J., Goltz, J.S., Konsolaki, M., SchŸpbach, G., and Stein, D. Windbeutel is required for function and subcellular localization of the Drosophila patterning protein Pipe. Development, In press (2000).

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