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 the Notch and abl signaling pathways in order to understand how a receptor controls axon extension and guidance. In order to understand the Notch/abl pathway and how it controls axon growth and guidance, the specific aims of the project include: a cellular analysis of Notch/abl-dependent axon extension; investigation of the genetic interactions among known members of the Notch and abl signaling pathways; a detailed biochemical analysis of the interactions among the central constituents of the pathway (NOTCH, ABL and the ABL accessory protein, DISABLED); and in vivo tests of models we derive for the structure of the Notch/abl signaling pathway. abl and Notch are widely expressed, phylogenetically conserved and implicated in a variety of developmental processes both in vertebrates and invertebrates. 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. Human Abl and Notch are both associated with human diseases, including particular cancers. The discovery that they are two parts of the same regulatory pathway has the potential to unify a large mass of confusing data into a single, coherent mechanism, and so to change the way we think about diseases in which both genes are implicated, such as acute leukemia.
| Le Gall, Maude; De Mattei, Cordell; Giniger, Edward (2008) Molecular separation of two signaling pathways for the receptor, Notch. Dev Biol 313:556-67 |
| Connell-Crowley, Lisa; Vo, Duc; Luke, Lori et al. (2007) Drosophila lacking the Cdk5 activator, p35, display defective axon guidance, age-dependent behavioral deficits and reduced lifespan. Mech Dev 124:341-9 |
