Background

It is now well-known that environmental cues guide axons to their targets during development. This was first shown in the 1940s it by Roger Sperry, whose ground-breaking experiments on amphibian visual systems showed that after severing and removal of axons; they would regenerate and always grow back directly to the right place in the brain. This formed Sperry’s chemoaffinity hypothesis. He suggested that axons were guided towards a target by following individual chemical codes carried by the cells in the embryo. These chemical codes have since been termed as guidance cues, and many different families have been identified.

Guidance Cues

There are four primary forces involved with axon guidance. These are either diffusible or surface bound molecules which attract or repel growing axons.

Thus the temporal and spatial presence of these guidance molecules act as cues in the embryo, almost like a series of ‘signposts’ for the travelling axon. During its journey an axon will encounter a combination of all four guidance forces. It is the role of the growth cone to ensure that these cues are interpreted correctly, in order for the axon to reach its correct target. The growth cone responds to each type of cue in differently. Simply put, the growth cone will turn towards an attractive cue, but turn or collapse away from a repulsive cue. 

The surface bound, contact dependant guidance cues generally provide the axons with a permissive substrate on which to grow, as well as local guidance. Whereas the concentration gradients created by the diffusible molecules act as long-distance guidance for the axons.

Guidance molecules include Ephrin, Netrin, Semaphorin and the Slit protein families. All of these have been studied in many different organisms and their actions are well characterized.