Guidance Molecules in Axon Regeneration

The adult mammalian central nervous system (CNS) has limited regenerative capacity, leading to permanent neurological deficits after injury. Spinal cord injury (SCI) interrupts crucial nerve pathways. A major research goal is to restore these pathways, but the inhibitory nature of adult CNS tissue hinders axonal regrowth. CNS inhibitors include axon guidance molecules (semaphorins, ephrins, netrins), myelin inhibitors (Nogo, MAG, OMgp), and chondroitin sulfate proteoglycans. Conversely, extracellular matrix molecules, cell adhesion molecules, and neurotrophic factors promote growth. Combination therapies targeting both inhibitory and promoting pathways show promise in animal models. Following peripheral nervous system (PNS) injury, sensory and motor axons can regenerate over long distances. Conversely, after CNS injury, severed axons show very limited regeneration. Some populations of adult CNS neurons retain a capability for long-distance axon growth throughout adulthood, if provided with a favorable growth environment.

• 1
  Axon guidance molecules, initially important for neural development, are also present in the mature CNS, influencing network refinement, neuronal excitability, and synaptic function.
• 2
  Injured CNS tissue up-regulates inhibitory guidance cues like semaphorins and ephrins, contributing to the failure of axonal repair. Blocking these inhibitory molecules shows promise in promoting axonal growth in vitro and in vivo.
• 3
  Myelin inhibitors (Nogo, MAG, OMgp) contribute to growth inhibition in the CNS. While deletion or neutralization of these inhibitors alone shows limited corticospinal axon regeneration, targeting these pathways is under translational human testing in acute SCI.