The cellular and molecular basis of axonal growth.

Introduction. During embryonic and post-natal development, numerous axonal connections are formed establishing a functional nervous system. Knowledge of the underlying molecular and cellular mechanisms controlling this phenomenon is improving. State of the art. In this review, we present the general principles of axon guidance together with the major families of guidance signals. This includes the tyrosine kinase receptors Eph and their ligands Ephrins, the netrins, the semaphorins, the slits and other major components of the extracellular matrix. These types of guidance signals share common functional properties leading to actin cytoskeleton remodelling. The direct or indirect interactions between the receptors of these guidance cues and actin modulators is the final step of the signalling cascade constituting the fundamental mechanism defining the orientation and extension of the axonal growth cone. These factors are involved in the formation of many, if not all, axonal projections for which they act as repulsive (inhibitory) or attractive (promoting) signals. Perspectives. the knowledge of these mechanisms is particularly interesting since the inhibition of axonal outgrowth is considered to be one of the major obstacles to nerve regeneration in the central nervous system. Indeed, most of the guidance signals expressed during brain development are up-regulated in lesion sites where they contribute to the lack of nerve re-growth. Here, we present the nature of the mechanical barrier, the so called glial scar, and we describe the major inhibitory molecules preventing axonal extension. Conclusion. the comprehension of the molecular mechanisms involved in axon growth and guidance represents a major advance towards the definition of novel therapeutic strategies improving nerve regeneration. The path to the clinical application of these molecular factors remains long. Nevertheless, the next decade will undoubtedly provide challenging data that will modify the current therapeutic approaches.