Axon Guidance and Olfactory Map Development

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Topographic maps are the means by which all sensory systems process afferent information. Hence, finding the molecules that regulate topographic map development is a pressing issue in neurobiology. Classically, projections of retinal axons to the brain has provided a model for the investigation of neural maps where there is direct, point- to-point mapping of the peripheral receptor sheet onto the map. However, development of maps with a different organization, like the olfactory map, is poorly understood. Olfactory neurons responsive to different odors are interspersed in the receptor sheet. Yet they project their axons with great precision to specific targets (glomeruli) in the brain. The molecular mechanisms by which olfactory fibers navigate to their targets, e.g. guidance cues and their signaling mechanisms, are essentially unknown. The long-term goal of my laboratory is to elucidate the molecular and cellular mechanisms of olfactory axon guidance and odotopic map development, using Drosophila as a model system. Our preliminary data indicated that two signaling molecules that are involved in cytoskeletal control and cellular motility, Dock (an SH2/SH3 adapter) and Pak (a serine/threonine kinase), are required for precise targeting of the fly olfactory axons. In this proposal, we hypothesize that Dock and Pak act in a signal transduction cascade to precisely steer olfactory growth cones to their targets. Our specific aims are to: 1) Identify the exact cellular events regulated by Dock and Pak in olfactory axons. This will be carried out through detailed phenotypic analyses of the dock and Pak mutants using a variety of cell-fate and subcellular markers. 2) Delineate the molecular mechanisms of Dock and Pak's function. This will be achieved through structure-function studies, and genetic epistatic analyses of dock and Pak genes in olfactory axon guidance. 3) Determine if Lim-Kinase (a serine/threonine kinase) is a novel signaling component downstream of Pak. This will be assessed through in vitro kinase assays with purified proteins, and analyses of the genetic interactions between Pak and Lim- kinase genes in the projections of olfactory axons. These experiments are expected to provide critical insights, and the first glimpse into the molecular mechanisms of olfactory growth cone steering and olfactory map formation.