Searching for guidance cues: follow the Sidestep trail

Neuronal growth cones migrate along stereotypic pathways to find and select their correct targets. Although it is widely believed that attractive and repulsive guidance molecules provide directional cues for migrating growth cones, it is still only poorly understood how these factors cooperate in a spatial and temporal manner. We have recently proposed that Drosophila motor axons recognize and follow a Sidestep-labeled substrate pathway from the ventral nerve cord to their peripheral target muscles. Sidestep (Side) is a transmembrane protein of the immunoglobulin superfamily and functions as a target-derived attractant. On motor axons, Beaten path Ia (Beat) is required to detect Side. In addition, Beat interacts with Side both genetically and biochemically, leading to the formation of heterophilic adhesion complexes in vitro. Since Side is expressed in sensory neurons, Beat-expressing motor axons fasciculate with sensory axons and use them as migratory substrates. In a similar process, motor axons contact a subset of Side-expressing glial cells, demonstrating that, during the period of axonal pathfinding, motor axons interact with all cell types that later will be the major constituents of peripheral nerves. Here, I discuss the idea that Sidestep-mediated attraction might represent the initial step for the controlled assembly of peripheral nerves.