The virtuous cycle of axon growth: Axonal transport of growth-promoting machinery as an intrinsic determinant of axon regeneration

Abstract

Injury to the brain and spinal cord has devastating consequences because adult central nervous system (CNS) axons fail to regenerate. Injury to the peripheral nervous system (PNS) has a better prognosis, because adult PNS neurons support robust axon regeneration over long distances. CNS axons have some regenerative capacity during development, but this is lost with maturity. Two reasons for the failure of CNS regeneration are extrinsic inhibitory molecules, and a weak intrinsic capacity for growth. Extrinsic inhibitory molecules have been well characterised, but less is known about the neuron-intrinsic mechanisms which prevent axon re-growth. Key signalling pathways and genetic / epigenetic factors have been identified which can enhance regenerative capacity, but the precise cellular mechanisms mediating their actions have not been characterised. Recent studies suggest that an important prerequisite for regeneration is an efficient supply of growth-promoting machinery to the axon, however this appears to be lacking from non-regenerative axons in the adult CNS. In the first part of this review, we summarise the evidence linking axon transport to axon regeneration. We discuss the developmental decline in axon regeneration capacity in the CNS, and comment on how this is paralleled by a similar decline in the selective axonal transport of regeneration-associated receptors such as integrins and growth factor receptors. In the second part, we discuss the mechanisms regulating selective polarised transport within neurons, how these relate to the intrinsic control of axon regeneration, and whether they can be targeted to enhance regenerative capacity.