The N-terminal leucine-rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neurons.

The Slit proteins are a new family of secreted guidance cues involved in axon guidance and neuronal migration. Each mammalian Slit protein contains >1400 amino acid residues, with four leucine-rich regions (LRRs), nine epidermal growth factor repeats, a laminin G domain, and a C-terminal cysteine-rich domain. A receptor for Slit is the transmembrane protein Roundabout (Robo), whose extracellular part contains five Ig domains and three fibronectin type III repeats. We report here that the LRRs in Slit are sufficient for binding to the Ig domains of Robo. Mutant forms of Slit containing only the LRRs function as chemorepellents for axons projecting from the olfactory bulb both in vitro and in the telencephalon. The LRRs can repel neurons migrating from the anterior subventricular zone (SVZa) to the olfactory bulb in brain slices isolated from neonatal rodents. However, the LRRs do not show repulsive effects on the SVZa neurons migrating in collagen gels. Our results indicate that the same LRRs are sufficient for guiding both axon projection and neuronal migration and suggest that the other regions in the Slit proteins may be involved in regulating the diffusion and distribution of the Slit proteins. The fact that the same domains are involved in guiding axon projection and neuronal migration further strengthens the idea of a conserved guidance mechanism for these important processes.