GENES ESSENTIAL TO MOTOR AXON GUIDANCE IN DROSOPHILIA

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DESCRIPTION (From the Applicant's Abstract): The long-term goal of these studies is to understand the fundamental molecular mechanisms that guide axons to their correct targets in vivo. These mechanisms are vital not only for establishing the complex functional architecture the nervous system, but also for repairing the network of connections following neural injury. Therefore, knowledge gained from this work is likely to provide tools for the development of future therapeutic approaches to neurological disease and trauma. Although rapid progress has been made in the identification of many extracellular factors and corresponding receptors that control axonal growth, far less is known about the intracellular machinery that interprets this information and translates it into the accurate directional motility of individual growth cones. We have exploited Drosophila as a model system to identify signaling components that function in concert to guide embryonic axons. Our recent work has defined part of an emerging pathway of proteins that appear to link multiple signals at the cell surface with the dynamic remodeling of leading edge cytoskeleton. This putative pathway includes several highly conserved proteins known to bind and/or regulate actin assembly in different systems; this includes Enabled (Ena), Profilin, the Rac-activator Trio, and a member of the Cyclase-Associated Protein family called Capulet (Capt). Our current data suggests a model where the activity of these associated components are controlled by an antagonistic partnership between the receptor protein tyrosine phosphatase Dlar and the protein tyrosine kinase Abl. However, the precise mechanism involved in the link between cell surface and cytoskeleton, and the means by which it is controlled by tyrosine phosphorylation, is not known. In the past few years we have defined a number of different assays to explore the function, interaction and regulation of this signaling pathway both in vitro and in vivo. We will use these assays to explore several issues: First: are Ena, Capt, Profilin and Trio downstream of Diar and Abi activity? Second: what is the nature of physical association between the components in cellular extracts, and how are these associations regulated by tyrosine phosphorylation? Third: are the physical associations between Ena, Capt, Profilin and Actin required for the output of Dlar and Abl in vivo, or for cytoskeletal structure in cultured cells? And, fourth: how does the function of each signaling component influence the dynamic behavior of developing growth cones? Parallel studies at these different levels of resolution will be important if we are to understand this mechanism in detail.