Faculty and Research
Faculty by Name
David Bilder
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David Bilder
Associate Professor of Cell and Developmental Biology*
*And Affiliate, Division of Genetics and Development
Research Interests
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Epithelial Architecture: Polarity, Trafficking, and Tumor Suppression
Metazoan animals contain a bewildering variety of cell types whose forms are highly specialized for their functions. Yet how cells adopt these diverse shapes and structures remains mysterious. We are exploring this fundamental question of cell biology using a simple cell type — epithelia — in a genetically manipulable organism —Drosophila. We have adapted targeted mosaic techniques to screen, in vivo and in an unbiased manner, for genes required for cells to assume the highly regular epithelial organization. Cloning and characterization of these genes will reveal the mechanisms that regulate general cellular elements, such as the cytoskeleton and protein trafficking systems, in order to confer specific cellular architectures. Since epithelial organization is compromised during the progression of mammalian malignant tumors, we also study how polarity disruption in the fly can promote the acquisition of cancer-like cellular properties. We expect this research in a model organism to inform studies of cancer and other human diseases.
Current Projects
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Current research focuses on three questions:
1). How is the polarity of epithelial cells established and maintained?
We have carried out several screens to identify mutations that disrupt apicobasal polarity of embryonic, imaginal, and adult epithelia. These screens have led us to the study of the 'neoplastic tumor suppressor genes' (nTSGs): discs-large, lethal giant larvae, and scribble. The nTSGs encode proteins that act to distinguish the basolateral domain of epithelia by antagonizing the activity of the apical Baz/Par-3 complex. We are studying the mechanisms by which the nTSGs polarize tissue, using cell biological assays of protein trafficking and biochemical studies of nTSG partners.
Our recent cloning of a new set of nTSGs identified in the lab has revealed that these encode regulators of the endocytic protein trafficking pathway. Studies of protein trafficking and the particular trafficked receptors relevant to polarity determination are in progress. Interestingly, mutations that disrupt distinct endocytic stages also lead to differential hypo- or hyperactivation of various cell signaling pathways; we are investigating the mechanisms of activation in each case. Finally, genetic screens to identify further mutations that regulate epithelial polarity and signal transduction are underway.
2). How can misregulation of epithelial polarity led to tumor formation?
A fascinating feature that distinguishes the nTSGs from other polarity regulators is that mutations in them also cause the formation of tumorous growths in the fly. These fly tumors share a number of characteristics with malignant mammalian tumors, including an inability to exit the cell cycle, failure to differentiate, loss of eptihelial structure, and the acquisition of invasive capabilities echoing metastasis. We are studying the signaling pathways that instruct cells as well as entire tissues to cease proliferation and undergo terminal differentiation, and are investigating why these signals require polarized cell architecture for proper transduction. To shed further light on this subject, we have initiated a set of novel screens to identify new molecules that regulate both epithelial polarity and proliferation.
3). What molecules control the shape, organization, and movement of epithelial tissues?
In our screens for polarity mutants, we also frequently identify mutations that disrupt various aspects of epithelial morphogenesis. By creating genetic mosaics in the easily accessible follicle cell epithelium, we can study the mechanisms underlying for instance the transitions between squamous, cuboidal, and columnar cell shapes, the concerted migration of epithelial sheets, and other aspects of organ morphogenesis. Cloning of the genes associated with morphogenetic mutations will provide us with an entry point into elucidating the cell biological processes that underlie these critical developmental events.
Selected Publications
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Vaccari, T., Lu, H., Kanwar, R., Fortini, M.E., and D. Bilder (2008). Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. Journal of Cell Biology, 180(4):755-62.
Horne-Badovinac, S. and D. BIlder (2008). Dynein regulates epithelial polarity and the apical localization of stardust A mRNA. PLoS Genetics, 4(1):e8.
Menut, L., Vaccari, T., Dionne, H., Hill, J., Wu, G., and D. Bilder (2007). A mosaic genetic screen for Drosophila neoplastic tumor suppressor genes based on defective pupation. Genetics, 177(3):1667-77.
Hariharan, I.K. and D. Bilder (2006). Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annual Review of Genetics, 40:335-61.
Lu, H. and D. Bilder (2005). Endocytic control of epithelial polarity and proliferation in Drosophila. Nature Cell Biology, 7(12): 1132-9.
Vaccari, T. and D. Bilder (2005). The Drosophila tumor suppressor vps25 prevents non-autonomous overproliferation by regulating Notch trafficking. Developmental Cell, 9(5): 687-98.
Horne-Badovinac, S. and D. Bilder (2005). Mass transit: Epithelial morphogenesis in the Drosophila egg chamber. Developmental Dynamics 232(3): 559-574.
Zeitler, J., Hsu, C.P., Dionne, H. and D. Bilder (2004). Domains controlling polarity and proliferation in the Drosophila tumor suppressor Scribble. Journal of Cell Biology 167(6): 1137-1146.
Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors . [D. Bilder (2004) Genes and Development 18 :1909-25]
Integrated activity of PDZ protein complexes mediates the maturation of epithelial polarity. [D. Bilder, M. Schober, and N. Perrimon (2003) Nature Cell Biology 5:53-8]
Polarity determination in breast tissue: desmosomal adhesion, myoepithelial cells, and laminin 1. [M. J. Bissell and D. Bilder (2003) Breast Cancer Research 5:117-9]
Recruitment of Scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein. [D. Mathew, L.S. Gramates, M. Packard, D. Bilder, N. Perrimon, M. Gorczyca and V. Budnik (2002) Current Biology 12 :531-9]
PDZ proteins and polarity: functions from the fly. [D. Bilder (2001) Trends in Genetics 17: 511-8]
Cell polarity: squaring the circle. [D. Bilder (2001) Current Biology 11:R132-5]
Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors.[Bilder, D., M. Li, and N. Perrimon (2000). Science 289 : 113-6. [cf comment in Science 289: 67-9, Current Biology 10: R624-6]]
Collective nomenclature for LAP proteins. [D. Bilder, D. Birnbaum, J.P. Borg, P. Bryant, J. Huigbretse, E. Jansen, M. B. Kennedy, M. Labouesse, R. Legouis, B. Mechler, N. Perrimon, M. Petit and P. Sinha (2000) Nature Cell Biology 2: E114]
Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. [D. Bilder and N. Perrimon (2000) Nature 403: 676-80 [cf comment in Nature 403:611-2]]
Last Updated 2009-02-18