Repulsive axon guidance: Abelson and enabled play opposing roles downstream of the roundabout receptor

Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Little is known about the signaling mechanisms which function downstream of Robe to mediate repulsion. Here, we present genetic and biochemical evidence that the Abelson (Abl) tyrosine kinase and its substrate Enabled (Ena) play direct and opposing roles in Robe signal transduction. Genetic interactions support a model in which Abl functions to antagonize Robe signaling, while Ena is required in part for Robe's repulsive output. Both Abl and Ena can directly bind to Robo's cytoplasmic domain. A mutant form of Robe that interferes with Ena binding is partially impaired in Robe function, while a mutation in a conserved cytoplasmic tyrosine that can be phosphorylated by Abl generates a hyperactive Robe receptor.