There are two most common models to study axon guidance: commissures and topographic maps.
1, Commissures are sites where axons cross the midline from one side of the nervous system to the other.
As described above, axonal guidance cues are often categorized as "attractive" or "repulsive.", but this is too simple to model the same axonal growth cone can alter its responses to a given cue based on timing. These issues are exemplified during the development of commissures. The bilateral symmetry of the nervous system means that axons will encounter the same cues on either side of the midline. Before crossing (ipsilaterally), the growth cone must navigate toward and be attracted to the midline. However, after crossing (contralaterally), the same growth cone must become repelled or lose attraction to the midline and reinterpret the environment to locate the correct target tissue.
Two experimental systems have had particularly strong impacts on understanding how midline axon guidance is regulated:
1.1 The ventral nerve cord of Drosophila
The use of powerful genetic tools in Drosophila led to the identification of a key class of axon guidance cues, the Slits, and their receptors, the Robos (short for Roundabout). The ventral nerve cord looks like a ladder. There are two commissures, anterior and posterior, within each segment of the embryo.
The currently accepted model is that Slit, produced by midline cells, repels axons from the midline via Robo receptors. Ipsilaterally projecting (non-crossing) axons always have Robo receptors on their surface, while commissural axons have very little or no Robo on their surface, allowing them to be attracted to the midline by Netrins and, probably, other as-yet unidentified cues. After crossing, however, Robo receptors are strongly upregulated on the axon, which allows Robo-mediated repulsion to overcome attraction to the midline. This dynamic regulation of Robo is at least in part accomplished by a molecule called Comm (short for Commissureless), which prevents Robo from reaching the cell surface and targeting it for destruction (before reaching to the middle line).
1.2 The spinal cord of mice and chickens
In the spinal cord of vertebrates, commissural neurons from the dorsal regions project downward toward the ventral floor plate (neuron reside at the dorsal part, detial seen in the figure below). Ipsilateral axons turn before reaching the floor plate to grow longitudinally, while commissural axons cross the midline and make their longitudinal turn on the contralateral side. Strikingly, Netrins, Slits, and Robos all play similar functional roles in this system as well. One outstanding mystery was the apparent lack of any comm gene in vertebrates. It now seems that at least some of Comm's functions are performed by a modified form of Robo called Robo3 (or Rig1).
2, Topographic maps
Topographic maps are systems in which groups of neurons in one tissue project their axons to another tissue in an organized arrangement such that spatial relationships are maintained.
In the simplest type of mapping model (retina neuron project to optic tectum), we could imagine a gradient of Eph receptor expression level in a field of retina neurons with the anterior cells expressing very low levels and cells in the posterior expressing the highest levels of the receptor. Meanwhile, in the target of the retinal cells (the optic tectum), Ephrin ligands are organized in a similar gradient: high posterior to low anterior. Retinal axons enter the anterior tectum and proceed posteriorly. Because, in general, Eph-bearing axons are repelled by Ephrins, axons will become more and more reluctant to proceed the further they advance toward the posterior tectum. However, the degree to which they are repelled is set by their own particular level of Eph expression, which is set by the position of the neuronal cell body in the retina. Thus, axons from the anterior retina, expressing the lowest level of Ephs, can project to the posterior tectum, even though this is where Ephrins are highly expressed. Posterior retinal cells express high Eph level, and their axons will stop more anteriorly in the tectum.
