The long-term goal of this research project is to elucidate the constituents and functional organization of signaling pathways that control directed cell motility. In the context of neural development, directed cell movement is necessary for the appropriate positioning of cell soma, and for the precise map of axonal connections between different populations of neurons. Studies in different systems suggests that such pathways form a link between signals at the cell surface and the dynamic cytoskeleton that drives forward movement. Among many proteins implicated in the cellular motility machinery, protein tyrosine kinases (PTKs) are key regulators of axon guidance. Previous work on the Drosophila PTK abl, orthologue of the vertebrate Abelson proto- oncogene, identified Disabled (dab), an abl-interacting phosphoprotein required for axonal development. Recent studies have shown that the mammalian counterpart of dab (mdab) plays a crucial role in the neuronal cell migration that underlies corticogenesis. These data suggest that a thorough understanding of the Abl pathway may provide tools and treatments relevant not only oncogenesis, but also for disease and injury of the nervous system. Unfortunately, the molecular events that mediate the cell motility functions of abl and dab are not understood in any system. We have designed and implemented a genetic screen for novel components in the Abl pathway and have identified several new loci that interact with abl and dab. One of these genes (filamin) is known to bind both cell surface receptors and actin cytoskeleton, and is required for cortical neuron migration in humans. Having established a functional assay for the role of abl in axon outgrowth, we will first dissection the structural features of abl necessary for this role. An equivalent analysis of dab will be pursued in parallel. Having discovered a genetic interaction between dab and filamin, and axonal phenotypes in filamin mutants,. Our second goal will be to define the relationship between filamin and other abl pathway components, and to dissect the contribution to define the relationship between filamin and other abl pathway components, and to dissect the contribution of different structural domains to the function of filamin during axogenesis. Finally, we have identified tetanic as a gene required for axonal development that interacts with both abl and dab. Thus, our third goal will be to determine the sequence of the tetanic gene and to explore the genetic and biochemical interactions between tetanic and other pathway components in order to define its mechanism of action within the developing nervous system.
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