During nervous system development, neurons extend axons to reach their targets and form functional circuits. The faulty assembly or disintegration of such circuits results in disorders of the nervous system. Thus, understanding the molecular mechanisms that guide axons and lead to neural circuit formation is of interest not only to developmental neuroscientists but also for a better comprehension of neural disorders. Recent studies have demonstrated how crosstalk between different families of guidance receptors can regulate axonal navigation at choice points, and how changes in growth cone behaviour at intermediate targets require changes in the surface expression of receptors. These changes can be achieved by a variety of mechanisms, including transcription, translation, protein-protein interactions, and the specific trafficking of proteins and mRNAs. Here, I review these axon guidance mechanisms, highlighting the most recent advances in the field that challenge the textbook model of axon guidance.
our knowledge of neural circuit formation in the brain is still very much in its infancy. We can infer molecular mechanisms from what we have learned in one system to another but there is still not a single population of axons for which we have a complete understanding of the molecular mechanisms of navigation to the final target. So, we are clearly not there yet! A major challenge remains the characterization of the precise temporal regulation of guidance signals and the interactions between different signalling pathways that cooperate to guide axons to their intermediate, and ultimately final, targets. Axon guidance studies in a variety of organisms clearly indicate that the regulation of axon guidance signalling involves all possible mechanisms of regulation: transcriptional and translational control, trafficking of specific vesicles, and changes in protein-protein interactions as well as protein stability. Furthermore, the link between the interactions of guidance receptors and their ligands with the observed behaviour of growth cones is still missing. We also only have a very superficial understanding of the association between surface receptors and the regulation of cytoskeletal dynamics responsible for steering growth cones (Gomez and Letourneau, 2014). Similarly, our knowledge on specific intra-axonal trafficking of signals is poor. To make the next step in our understanding of axon guidance, it will be important to keep complexity in mind. Classical loss-of-function approaches might not reveal the complex interaction between guidance cues and their different receptors. Precise temporal control of experiments during embryonic development is difficult in mammals. Therefore, it will be important to make use of diverse animal models, each with its strengths and weaknesses. A particular challenge will be the visualization of the functional link between surface receptors and the cytoskeleton. This is becoming easier to do in vitro thanks to high-resolution imaging techniques, but in vitro experiments will not allow for the analysis of axon guidance as they will never be able to mimic the complexity of cell-cell interactions in the developing tissue. It is thus clear that understanding axon guidance remains a challenge, and that a multifaceted, multidisciplinary approach will be required to understand not only how a single axon finds its target but how billions of axons manage to do so.
Common Design 