Signal transduction in neuronal migration: Roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway

The Slit protein guides neuronal and leukocyte migration through the transm embrane receptor Roundabout (Robo). We report here that the intracellular d omain of Robo interacts with a novel family of Rho GTPase activating protei ns (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions resp onsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc 42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) o f the forebrain. A constitutively active Cdc42 blocked the repulsive effect of Slit. These results have demonstrated important roles for GAPs and Cdc4 2 in neuronal migration. We propose a signal transduction pathway from the extracellular guidance cue to intracellular actin polymerization.