Intracellular Trafficking Mechanisms that Regulate Repulsive Axon Guidance

Friedrich Bonhoeffer made seminal contributions to the study of axon guidance in the developing nervous system. His discoveries of key cellular and molecular mechanisms that dictate wiring specificity laid the foundation for countless investigators who have followed in his footsteps. Perhaps his most significant contribution was the cloning and characterization of members of the conserved ephrin family of repulsive axon guidance cues. In this review, we highlight the major contributions that Bonhoeffer and his colleagues made to the field of axon guidance, and discuss ongoing investigations into the diverse array of mechanisms that ensure that axon repulsion is precisely regulated to allow for accurate pathfinding. Specifically, we focus our discussion on the post-translational regulation of two major families of repulsive axon guidance factors: ephrin ligands and their Eph receptors, and slit ligands and their Roundabout (Robo) receptors. We will give special emphasis to the ways in which regulated endocytic trafficking events allow navigating axons to adjust their responses to repellant signals and how these trafficking events are intimately related to receptor signaling. By highlighting parallels and differences between the regulation of these two important repulsive axon guidance pathways, we hope to identify key outstanding questions for future investigation.