Mechanisms of Axon Growth and Regeneration: Moving between Development and Disease

Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to grow and therefore fail to regenerate. Recent progress has enabled a better understanding of how developmental mechanisms direct axon regeneration. Focusing on neuronal polarization, where one neurite is singled out to become the axon, has uncovered the mechanisms initiating axon growth and growth restraint. This has helped to define the processes that need to be reactivated to induce axon regeneration: microtubule stabilization and actin dynamics. The molecular machinery underlying axon growth and axon regeneration is remarkably similar and includes the Rho-GTPases Cdc42, Rac-1, and RhoA, as well as the actin regulators cofilin and Myosin II. Importantly, neuron-intrinsic growth inhibitors in the adult nervous system, including the voltage-gated calcium channel subunit α2δ2 and the presynaptic active zone protein Munc13, restrain dynamics while the components driving axon growth remain largely present. The identified molecules suggest that synaptic transmission and axon growth may be processes that exclude each other. As a result, axon regeneration may be hampered by synaptic transmission and, thus, by the maturation of the CNS. This research has led to several translational avenues to induce axon regeneration and functional recovery after spinal cord injury and stroke; these include the drugs epothilones, gabapentinoids, and baclofen. Thus, the investigation of axon growth and regeneration side by side has been instrumental to coax the regenerative potential of the CNS.