The specific targeting of guidance receptors within neurons: who directs the directors?

Guidance molecules present in both axonal and dendritic growth cones mediate neuronal responses to extracellular cues thereby ensuring correct neurite pathfinding and development of the nervous system. Little is known though about the mechanisms employed by neurons to deliver these receptors, specifically and efficiently, to the extending growth cone. A deeper understanding of this process is crucial if guidance receptors are to be manipulated to promote nervous system repair. Studies in other polarised cells, notably epithelial, have elucidated fundamental routes to the intracellular segregation of molecules mediated by endosomal pathways. Due to their extreme complexity and specialisation, neurons appear to have built upon these generic systems to evolve sophisticated trafficking networks. A striking feature is the axon initial segment which acts like a valve to tightly regulate the flux of molecules both entering and leaving the axon. Once in the growth cone, further controls operate to enhance the retention or rejection, as appropriate, of membrane receptors. We discuss the current state of knowledge regarding the intracellular trafficking of axon guidance receptors and how this relates to their developmental roles. We highlight the various facets still to be properly elucidated and by building on existing data regarding neuronal polarity and intracellular sorting mechanisms suggest ways to fill these gaps.