Professor of Cell and Developmental Biology*
*And Affiliate, Division of Genetics and Development
Epithelial Architecture: Polarity, Tumor Suppression, and Morphogenesis
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 cell and tissue 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.
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 Par/aPKC 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, which encode regulators of endocytosis, has provided insight and led to studies of the particular trafficked receptors relevant to polarity determination and the interface with scribble-class neoplastic TSGs. Finally, genetic screens to identify additional genes that regulate epithelial polarity are underway.
How does epithelial polarity influence tumorigenesis?
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 epithelial structure, and the acquisition of invasive capabilities echoing metastasis. Recent evidence supports a role of polarity in mammalian tumor suppression as well. 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. One revelation has been an interface with chromatin-modifying epigenetic regulators; we are studying how this mechanism may provide insight into the multifaceted and long-lasting character of neoplastic transformation.
What molecules control the shape, organization, and movement of epithelial tissues?
Our interest in epithelial morphogenesis extends beyond apicobasal polarity. By disrupting gene function in the easily accessible and developmentally dynamic follicle cell epithelium, we also study the mechanisms underlying other aspects of cell and organ architecture. Identification of new genes required for follicle morphogenesis provides an entry point; we combine these in vivo genetic manipulations with real-time imaging and ex vivo measurements, manipulations and modeling to uncover the cell biological processes that underlie critical and phylogenetically conserved developmental events.
O'Brien LE, Soliman SS, Li X and D Bilder (2011). Altered Modes of Stem Cell Division Drive Adaptive Intestinal Growth. Cell, 147: 603-614
Haigo SL and D. Bilder (2011). Global Tissue Revolutions in a Morphogenetic Movement Controlling Elongation. Science 331(6020):1071-4
Shivas JM, Morrison HA, Bilder D and AR Skop (2010). Polarity and Endocytosis: Reciprocal Regulation. Trends in Cell Biology, 20: 323-331.
Classen AK, Bunker BD, Harvey KF, Vaccari T, and D Bilder (2009), A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nature Genetics, 41:1150-5
Vaccari T, Lu H, Kanwar R, Fortini M and D Bilder (2008). Endosomal Entry Regulates Notch Receptor Activation in Drosophila. Journal of Cell Biology, 180: 755-62
Hariharan I and D Bilder (2006). Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annual Reviews of Genetics, 2006;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.
Zeitler J, Hsu C, 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.
Bilder D. (2004). Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes and Development 18: 1909-1925.
Bilder D, Schober M and N Perrimon (2003). Integrated activity of PDZ protein complexes mediates the maturation of epithelial polarity. Nature Cell Biology 5: 53-58
Bilder D, M Li and N Perrimon (2000). Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289 (5476): 113-6.
Bilder D and N Perrimon (2000). Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403 (6770): 676-80
Last Updated 2011-08-05