In nervous systems with symmetry about the midline, a substantial number of neurons project axons from one side to the other. Although several molecules have been identified that control whether or not an axon crosses the midline, until recently it has remained unknown how these same axons manage to choose the appropriate pathway in which to cross, a choice that is critical for nervous system function. In the Drosophila embryo, axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (Ac or PC, respectively). The Derailed (Drl) receptor tyrosine kinase is expressed on the growth cones and axons of all neurons that traverse the midline in the AC and acts as a guidance receptor for a repellent ligand present in the PC. The goal of this project is to understand how the Drl guidance mechanism functions to properly route axons across the midline. Regions of the Drl receptor required for signaling will be identified by testing a series of deletions and specific amino acid substitutions. A critical feature of Drl function is its down-regulation in growth cones and axons after they leave the AC. Using an in vivo assay, the regions of Drl required for its down-regulation will be defined. Drl's ligand, as well as components of the signal transduction pathway through which the Drl receptor acts in the growth cone, will be identified using genetic and biochemical strategies. There are likely to be other guidance receptors and ligands acting in concert with Drl to sort axons as they traverse the midline, and a prime candidate for such a molecule is Drl2, another member of the Drl family apparently expressed in PC neurons. The role of Drl2 in commissure choice will be defined by misexpression studies and by generating mutations in the gene. Finally, novel genes controlling commissure choice will be isolated in a genetic screen. Given the existence of vertebrate Drl homologs, plus the evolutionary conservation of other midline crossing components, it is possible that a Drl-like guidance mechanism will be operating in all complex nervous systems.
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