Dylan T. Burnette/ Nikon Small World.
The remarkable specificity of neuronal connectivity depends on accurate axon pathfinding during development. Pathfinding involves the detection of guidance cues in the environment by the growth cone, a motile chemotactic structure at the leading tip of the extending axon.
The growth cone was discovered over 100 years ago by Santiago Ramon y Cajal, the father of modern neuroscience. Cajal’s description of the growth cone (or cono de crecimiento) has not been bettered:
From the functional point of view, one might say that the growth cone is like a club or battering ram endowed with exquisite chemical sensitivity, rapid ameboid movements and a certain motive force allowing it to circumvent obstacles in its path, thus coursing between various cells until reaching its destination.
In the last 15 years, much progress has been made in our understanding of axon guidance. It is now know that guidance cues come in the form of membrane-bound adhesion molecules, which are either permissive or non-permissive for growth, and concentration gradients of soluble factors which are either attractive or repulsive.
The growth cone encounters many different guidance cues throughout its journey, and responds to each type of cue in a particluar way. Permissive cues allow outgrowth, while non-permissive cues are inhibitory and can cause growth cone collapse; an attractive cue causes the growth cone to turn towards it, and a repulsive cue causes it to collapse or turn away. Numerous guidance molecules have been identified, most notably the Ephrin, Netrin, Semaphorin and Slit protein families, whose functions have been well characterized in various organisms. (Tessier-Lavigne and Goodman, 1996).
Little is known about how guidance cues are presented in a timely manner, or about the mechanisms by which cues elicit growth cone responses. Although numerous studies have shown that local translation is crucial to the turning of growth cones in response to guidance cues (Lim and Holt, 2007), it has been unclear exactly which proteins are synthesized.
In parts 2 and 3, of this series, I will discuss three very recent studies which contribute further to our understanding of axon guidance. The first shows that, in at least one case, the growth cone cannot circumvent the obstacles in its path without the aid of a population of migrating neurons.
The second and third studies elucidate some of the mechanisms at work within in the growth cone as it turns towards or away from an attractive or repulsive guidance cue. Finally, in part 4, I put these recent studies into the context of axon guidance in general.
Lin, A. C & Holt, C. E. (2007). Local translation and directional steering in axons. EMBO J. 26: 3729-2736.
Tessier-Lavigne, M. & Goodman, C. S. (1996). The molecular biology of axon guidance. Science 274: 1123-1133.