Peripheral axon regeneration requires surface-expanding membrane addition. The continuous incorporation of new membranes into the axolemma allows the pushing force of elongating microtubules to drive axonal growth cones forward. Hence, a constant supply of membranes and cytoskeletal building blocks is required, often for many weeks. In human peripheral nerves, axon tips may be more than one metre away from the neuronal cell body. Therefore, in the initial phase of regeneration, membranes are derived from pre-existing vesicles or synthesised locally. Only later stages of axon regeneration are supported by membranes and proteins synthesised in neuronal cell bodies, considering the fastest anterograde transport mechanisms deliver cargo at 20 cm/day. While endo- and exocytosis of membrane vesicles are balanced in intact axons, membrane incorporation exceeds membrane retrieval during regeneration to compensate for the loss of membranes distal to the lesion site. Physiological membrane turnover rates will not be established before the completion of target re-innervation. In this review, the current knowledge on membrane traffic in axon outgrowth is summarised with a focus on endosomal vesicles as the provider of membranes and carrier of growth factor receptors required for initiating signalling pathways to promote the elongation and branching of regenerating axons in lesioned peripheral nerves.
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