The Abl tyrosine kinase plays a central role in the mechanism of axon extension, but the receptor(s) and signaling pathway that link Abl to extracellular guidance cues remain obscure. The receptor Notch controls the fates and morphologies of many cell types, but the signaling pathway by which it acts remains incompletely understood. We have recently shown that Notch interacts genetically and biochemically with the Abl signaling pathway to promote the extension of specific axons, in the developing Drosophila nervous system. The goal of our experiments is to unravel the link between Notch and Abl in order to understand how a receptor controls axon extension and guidance. We will first develop a model for the Notch/Abl signaling pathway by extending our biochemical and genetic analysis of the interactions between Notch, Abl, and the Abl accessory protein, Disabled. We will then test this model by constructing artificial signaling complexes in vivo and assaying their ability to function in the place of Notch and abl. The mechanism of axon guidance is one of the central unsolved problems in neural development. In recent years, a large number of guidance molecules have been identified, and a great deal learned about the cell biology of the growth cone. However, the molecular mechanisms by which guidance receptors couple to those first signaling proteins which initiate the process of axon extension have remained frustratingly elusive. Notch, Abl and Disabled now provide one of the only examples in which a receptor that is required for an identified axon guidance decision in vivo has been shown to bind directly to signaling proteins that are known genetically to be required in the axon for growth cone motility. They therefore afford a unique opportunity to dissect the mechanism of axon guidance in vitro and in vivo. Abl and Notch are widely expressed, phylogenetically conserved and implicated in a variety of developmental processes in vertebrates and invertebrates, as well as in human disease. The proposed experiments will reveal the connection between these two fundamental regulatory proteins, while also illuminating the mechanism of axon extension and the pathway that links a neuron's identity to its pattern of axonal projection.