Axonal Guidance

Abstract

Anatomical studies suggest that the billions of neurons that make up our brain are interconnected in a precise manner that is essential for their function. How do such connections form, given the long distances separating some neurons? How do topographically organized neuronal maps arise, allowing our brains to produce an internal representation of the outside world and the surface of our body? These questions were first asked over a century ago, and their answers center around a structure at the growing tip of axons called the growth cone. It is a highly motile cellular specialization, filled with receptors sensing a small number of diverse axon guidance signals. Such receptors are closely linked to the underlying cytoskeleton, allowing axon guidance signals to precisely and swiftly modulate actin and microtubules. Axon guidance signals are laid out along nerve trajectories and can be thought of as a set of navigation instructions that reduces a long journey into a series of discrete decision points. Some axon guidance signals are redeployed in the mature nervous system where they participate in its maintenance, regeneration, and synaptic function. Loss of function mutations in human genes encoding axon guidance molecules frequently cause structural brain abnormalities predicted by studies in model animals. However, an increasing number of complex neurological disorders are postulated to be caused by subtle defects in the development of neuronal connections. Such defects are often associated with slight variations in sequences of genes encoding axon guidance ligands and their receptors, bringing to light the fact that many nuances of their function still remain unknown.