Research / Clinical
Summary
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Diseases/Research Topics
Cell-cell Signaling
My laboratory is interested in the molecular mechanisms by which cell-cell signaling guides cell fate choices during Drosophila development. We are particularly interested in understanding how extracellular modulation of the EGF-R1 and TGFß-related Dpp2 signaling pathways influences cell fates during early nervous system formation in the embryo and during wing vein development in larval and pupal stages.
With respect to the Dpp signaling pathway, our focus is on an antagonist of Dpp signaling pathway encoded by a gene called short gastrulation (sog), which we cloned several years ago. During early embryonic development, dpp is expressed in the dorsal ectoderm, and sog is expressed in a complementary lateral domain comprising the future neuroectoderm. sog encodes a predicted secreted molecule (Sog) which is likely to diffuse from its site of production into neighboring regions, such as the dorsal non-neural region of the embryo3. In the neuroectoderm, where sog is expressed, it functions to protect cells from the neural suppressive action of Dpp, thereby providing a permissive condition for cells to follow the default pathway of neural development. This latter interaction between dpp and sog in defining neural versus non-neural ectoderm has been highly conserved during the course of evolution4 (see Figure). sog also antagonizes Dpp signaling during pupal wing vein development, but cannot do so in several other contexts such as pattering the anterior-posterior axis of the wing. We are now conducting structure-function analysis of the Sog protein and biochemical studies to understand mechanistically how Sog selectively blocks Dpp signaling during development.
Our primary interest in the EGF-R pathway is to understand the role and mechanism of action of a novel accessory molecule rhomboid (rho) which augments EGF-R signaling. rho gene encodes a membrane protein (Rho) which is concentrated in patches at the apical cell surface. Genes encoding most EGF-R pathway components are expressed ubiquitously, whereas rho is expressed only in or adjacent to cells requiring high levels of EGF-R signaling. The localized pattern of rho expression provides the spatial and temporal information to restrict hyperactive EGF-R signaling to appropriate cells. Recently, we have generated a large number of mutant rho alleles to define functional domains of Rho. We also are pursuing biochemical approaches to identify proteins which interact physically with Rho to promote EGF-R activity.
Another project related to both Dpp and EGF-R signaling is an analysis of wing vein development during larval and pupal stage. Wing vein development is a sensitive model developmental system for studying cell-cell signaling5. This is true, in part, because wings are non-essential structures. We have proposed that veins initially form at boundaries along the A/P axis at the interface of discrete domains of cells5. We have direct evidence supporting this model in the case of the second wing vein (see refs. in Web site). We hope to integrate our various studies to derive a mechanistic understanding of how modulation of the Dpp and EGF-R signaling pathways creates patterning information during development.
1. Bier, E. (1998). Localized activation of RTK/MAPK pathways during development. BioEssays 20: 189 -194.
2. Bier, E. (1997). Anti-neural inhibition: A conserved mechanism for neural induction. Cell 89: 681-684.
3. Biehs, B., François, V. and Bier, E. (1996). The Drosophila short gastrulation gene prevents Dpp signaling from autoactivating and suppressing neurogenesis in the neuroectoderm. Genes and Dev. 10: 2922-2934.
4. Schmidt, J., François, V., Bier, E. and Kimelman, D. (1995). The Drosophila short gastrulation gene induces an ectopic axis in Xenopus: evidence for conserved mechanisms of dorsal-ventral patterning. Development 121: 4319-4328.
5. Sturtevant, M.A. and Bier, E. (1995). Analysis of the genetic hierarchy guiding wing vein formation in Drosophila. Development 121: 785-801.
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