Distinguishing between directional guidance and motility regulation in neuronal migration

Although neuronal migration is an essential process in development, how neural precursors reach their final destination in the nervous system is not well understood. Secreted molecules that are known to be involved in axon guidance are likely to play important roles in regulating neuronal migration, but an important issue that remains unclear is whether such molecules act as directional guidance cues or as motility regulators in neuronal migration. The secreted protein Slit was initially suggested to be a repellent for migrating neurons (Wu et al., 1999). However, it was concluded recently that Slit plays an inhibitory rather than a repulsive role in neuronal migration (Mason et al., 2001). We have developed a series of assays that allow us to differentiate between repulsive and inhibitory effects of secreted molecules, and we demonstrate that Slit is a repellent capable of reversing the direction of neurons migrating either in culture or in their native pathways. We also show that although Slit reduces migratory speed under certain conditions, it can function as a repellent without concurrent inhibition of neuronal migration. This is the first study to clearly demonstrate that migrating neurons can be directionally guided by secreted molecules. These findings provide a basis to understand the physiological roles of secreted molecules in the developing nervous system and have implications on how they could be applied therapeutically. Our results also indicate that it should be possible to determine the specific action of other molecules as directional guidance cues or as motility regulators of cell migration.