Axon Guidance

What are the general mechanisms by which axons navigate to find a target area, including the different activities they might encounter?

For an organism to function correctly, it is necessary for its nervous system to be organized in a precise and complex way (Flanagan and Vanderhaeghen, 1998). Given that the nervous system is constituted of trillions of neurons that, on average, make connections with over a thousand other cells (Tessier-Lavigne and Goodman, 1996), the enormity of the task is difficult to overstate. This poses the question, therefore, of how such organization is achieved.

A major aspect of the development of the nervous system involves the projection of axons from groups of neurons towards specific targets. This typically occurs in a highly stereotyped and particular fashion, and there is evidence that suggests that errors associated with axon guidance are related to disorders such as autism (Anitha et al., 2008), as well as bipolar and schizophrenia (Mcintosh et al., 2008). In addition to the vast number of connections that are required to be formed between cells, the difficulty of organizing the nervous system is exacerbated by the relatively substantial distances that axons are required to travel - often thousands of times further than the diameter of the cell bodies from which they originate (Tessier-Lavigne and Goodman, 1996).

Ramon y Cajal (1892), who utilized Golgi`s staining method to examine axons, postulated that their navigation might be mediated via interactions between their growth cones (the name that he attributed to the hand-like structures at the distal end of axons) and extracellular guidance molecules. Specifically, he suggested that guidance could be orchestrated by long-range chemoattraction, whereby targets are able to elicit the growth of axons towards them by the secretion of guidance molecules.

Chemoattraction has since been demonstrated to constitute a major mechanism by which axons locate targets (Lumsden and Davies, 1983; Tessier-Lavigne et al., 1988). Crucially, guidance molecules are distributed within organisms along concentration gradients. Surrounding `guidepost` cells (Bentley and Caudy, 1983; those that secrete guidance molecules at final or intermediate targets) are the highest concentrations of guidance molecules; and with increasing distance from these, concentrations decrease (presumably, however, variables other than distance from secreting cells, such as the concentrations of other molecules, affect the concentration of a given molecular cue so that the distribution of cues is not perfectly symmetrical). Gradients are essential for chemoattraction in that they provide landscapes in which axons are essentially faced with different environments on either side, thus allowing them to `make decisions` regarding their trajectories.