The Logic and Mechanisms of Axon Guidance

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the subjects of this presentation. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in coordinated fashion to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems. This presentation will focus particularly on three families of guidance cues: the netrins, the semaphorins, and the slits. All of these proteins appear to be bifunctional, having attractive effects on some axons and repulsive effects on others. The functions of these proteins in directing particular guidance events in the developing mammalian nervous system will be discussed, as will the receptor and signal transduction mechanisms through which they produce their attractive and repulsive effects on growth cones. The analysis of signal transduction mechanisms has provided evidence recently that attraction and repulsion are closely related at a mechanistic level, as attractive responses can be converted to repulsive responses--and vice versa--by simple manipulations of signaling pathways. The picture that is starting to emerge from these studies is that the growth cone must contain within it a macromolecular machine that is similar to the engine of a motor car, capable of functioning in forward or in reverse, with different cues capable of accessing different states of the machine and different modulators capable of flipping the machine from one state to the other. Some recent advances in identifying components of this growth cone machine will be discussed.