Moving through the crowd. Where are we at understanding physiological axon growth?

Axon growth enables the rapid wiring of the central nervous system. Understanding this process is a prerequisite to retriggering it under pathological conditions, such as a spinal cord injury, to elicit axon regeneration. The last decades saw progress in understanding the mechanisms underlying axon growth. Most of these studies employed cultured neurons grown on flat surfaces. Only recently studies on axon growth were performed in 3D. In these studies, physiological environments exposed more complex and dynamic aspects of axon development. Here, we describe current views on axon growth and highlight gaps in our knowledge. We discuss how axons interact with the extracellular matrix during development and the role of the growth cone and its cytoskeleton within. Finally, we propose that the time is ripe to study axon growth in a more physiological setting. This will help us uncover the physiologically relevant mechanisms underlying axon growth, and how they can be reactivated to induce axon regeneration.