Ethan Bier
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There are two main branches of research in my laboratory. The first area of focus is in understanding how graded signaling mediated by the Bone Morphogenetic Protein (BMP) pathway subdivides the early Drosophila embryo into primary tissue types along the dorsal-ventral axis and then acts during larval stages to determine the position of wing veins. The second research area is to exploit genome-wide information to understand how gene regulatory networks form and function. One component of this latter effort is to use Drosophila as a tool for identifying and characterizing the function of human genes and bacterial pathogens that cause disease in humans. In collaboration with the McGinnis lab at UCSD we have also developed a highly sensitive method for multiplex in situ hybridization, which makes it possible to determine the relative expression patterns of large numbers of genes with great spatial and temporal resolution.
Dorsal-ventral Patterning in the Early Embryo: BMPs play three distinct roles in organizing the dorsal-ventral (D/V) axis of the Drosophila embryo. The first is their highly conserved function in subdividing the ectoderm (the outer embryonic germ layer) into neural versus epidermal domains. During this phase, BMP signaling actively represses neural cell fates in epidermal regions of the embryo [1]. In neuroectodermal regions of the embryo, invasion of autoactivating BMP signaling is blocked by the BMP antagonist Short Gastrulation (Sog) [2], which permits the default program of neural development to prevail [3]. As many of the pathway components required for neural induction are similarly deployed in vertebrates and invertebrates [4, 5], it seems highly likely that this similarity reflects the conservation of an ancestral mechanism for specifying neural versus epidermal cell fates.
Following their respective resident roles in consolidating cell fate choices within the epidermal and neural regions of the fly embryo during neural induction, Dpp and Sog also play non-autonomous roles in further subdivision of these two regions. Sog diffuses dorsally from the lateral neuroectoderm where it is cleaved and inactivated by the Tld protease in dorsal cells, resulting in the formation of a Sog protein gradient, that is higher ventrally and lower dorsally [6]. The Sog gradient creates an inverse BMP activity gradient with peak levels in dorsal-most cells, which in turn, subdivides the dorsal region into two parts: a dorsal-most extra-embryonic domain (amnioserosa), and a more ventral epidermal domain [7]. In addition, there is a reciprocal influence of Dpp diffusing ventrally, which contributes to partitioning the neuroectoderm into three primary rows of cells. As a consequence of Dpp being present in limiting amounts within the neuroectoderm its ability to repress expression of neural gene expression becomes dosage dependent [8]. In particular, BMP signaling represses expression of the mid-region neural identity gene ind more effectively than the dorsal neural identity gene msh. Since the Ind transcription factor cross-inhibits expression of msh, BMP-mediated repression of ind in dorsal neuroectodermal cells results in the de-repression of msh. Graded BMP-mediated repression may be an ancestral trait since BMPs also act in a dose dependent fashion to pattern the vertebrate neural tube.
Our current research in this area is focused on understanding the mechanisms for creating BMP activity gradients and in analyzing the cis-regulatory basis for differential sensitivity of genes to BMP mediated activation and repression.
Wing Vein Patterning: Wing veins are rigid hollow fluid conducting channels that function as structural supports for flight and as conduits bringing nutrients to sensory organs in the wing. The pattern of primary longitudinal veins is initiated along the borders of gene expression domains that form in response to the Hh and BMP morphogen gradients. Although formation of each vein is initiated separately, these linear structures are all induced by the same general mechanism (termed “for-export-only signaling”) in which cells in one domain produce a diffusible factor to which they are unable to respond [9]. The vein inducing signal diffuses into the adjacent cell territory where cells nearest the source of the signal can respond by activating expression of vein specific identity genes such as knirps (for the L2 vein) [10] or abrupt (for the L5 vein) [11]. We are currently most interested in identifying the for-export-only signals involved in L2 and L5 induction and in determining how vein identity genes confer vein specific traits.
Analysis of Human Disease Genes in Flies: The second major focus of my laboratory is to use Drosophila as a tool for analyzing the function of genes relevant to human disease [12]. As a first step in developing this new line of research, we conducted a comprehensive cross-genomic analysis of all human disease gene counterparts in Drosophila using the interactive Homophila database: (http://superfly.ucsd.edu/homophila/) [13]. This analysis revealed that 75% of all human disease genes have related sequences in Drosophila and that ≈ 30% of these genes (e.g., now nearly 900 genes) are as well conserved as genes known to be functionally equivalent between flies and vertebrates. These conserved Drosophila homologs represent a broad spectrum of human disease genes. Based on this analysis we initiated experimental studies to address specific questions in human genetics using the strengths of Drosophila, including: identifying protein targets of the UBE3A ubiquitin E3 ligase responsible for Angelman syndrome [14]; phenotypic analysis of antioxidant enzymes that interact with presenilin and may be involved in Alzheimer disease; and using flies as a model for analyzing host-pathogen interactions. For example, with regard to host-pathogen interactions we are analyzing the mechanism by which the two anthrax toxins Lethal Factor (LF) and Edema Factor (EF) collaborate to inhibit known and novel pathways [15].
Imaging Gene Expression: In collaboration with the McGinnis laboratory, Yoav Freund in computer Science, and clinicians at UCSD Medical School we are also developing new tools and applications for a fluorescence in situ hybridization method we developed (multiplex in situ hybridization) [16] for visualizing expression of several genes at a time in developing embryos and in tumor biopsy samples. These new experimental and computational tools should make it possible to visualize the expression patterns of many genes in normal tissues and in tumors to aid in the diagnosis and staging of cancer progression.
Bier, E., (1997). Anti-neural-inhibition: a conserved mechanism for neural induction. Cell, 89(5): 681-684.
Francois, V., et al., (1994). Dorsal-ventral patterning of the Drosophila embryo depends on a putative negative growth factor encoded by the short gastrulation gene. Genes Dev. 8(21): 2602-2616.
Biehs, B., V. Francois, and E. Bier, (1996). The Drosophila short gastrulation gene prevents Dpp from autoactivating and suppressing neurogenesis in the neuroectoderm. Genes Dev. 10(22): 2922-2934.
Francois, V. and E. Bier, (1995). Xenopus chordin and Drosophila short gastrulation genes encode homologous proteins functioning in dorsal-ventral axis formation. Cell 80(1):19-20.
Schmidt, J., et al., (1995). Drosophila short gastrulation induces an ectopic axis in Xenopus: evidence for conserved mechanisms of dorsal-ventral patterning. Development, 121(12): 4319-4328.
Srinivasan, S., K.E. Rashka, and E. Bier, (2002). Creation of a Sog morphogen gradient in the Drosophila embryo. Dev. Cell 2(1): 91-101.
Mizutani, C.M., et al., (2005). Formation of the BMP activity gradient in the Drosophila embryo. Dev. Cell 8(6): 915-924.
Mizutani, C.M., et al., (2006). Threshold-dependent BMP-mediated repression: A model for a conserved mechanism that patterns the neuroectoderm. PLoS Biology 4(10): e313.
Bier, E., (2000). Drawing lines in the Drosophila wing: initiation of wing vein development. Curr. Opin. Genet. Dev. 10(4): 393-398.
Lunde, K., et al., (2003). Activation of the knirps locus links patterning to morphogenesis of the second wing vein in Drosophila. Development 130(2): 235-248.
Cook, O., B. Biehs, and E. Bier, (2004). Brinker and optomotor-blind act coordinately to initiate development of the L5 wing vein primordium in Drosophila. Development 131(9): 2113-2124.
Bier, E., (2005). Drosophila, the golden bug, emerges as a tool for human genetics. Nat. Rev. Genet. 6(1): 9-23.
Reiter, L.T., et al., (2001). A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 11(6): 1114-1125.
Reiter, L.T., et al., (2006). Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Hum. Mol. Genet. 15(18): 2825-2835.
Guichard, A., et al. (2006). Anthrax lethal factor and edema factor act on conserved targets in Drosophila. Proc. Natl. Acad. Sci. U S A 103(9): 3244-3249.
Kosman, D., et al. (2004). Multiplex detection of RNA expression in Drosophila embryos. Science 305(5685): 846.
Ethan Bier received his Ph.D. from Harvard University. He has received the Sloan Foundation Award, the McKnight Award for Neuroscience, the Basil O'Connor Award, and the American Cancer Society Junior Faculty Award.
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