Stimulating axon regeneration after spinal cord or brain injury is a key problem in neuroscience research. Axons of the central nervous system (CNS) lose their regenerative ability with maturity, whereas peripheral nervous system (PNS) axons do not. A clue to the difference in the regenerative abilities of these neuronal types lies with integrins: integrins mediate PNS regeneration, but they are excluded from CNS axons, along with their Rab11 carriers, after development. In their Research Article on page 3663, James Fawcett and colleagues investigate whether restoring the ability of CNS axons to transport growth-promoting machinery boosts their intrinsic capacity for regeneration. The authors show that the ARF6 guanine-nucleotide-exchange factor (GEF) EFA6 is enriched in the axon initial segment and activates ARF6 throughout mature CNS axons. Furthermore, EFA6 directs integrins away from axons, as removing EFA6 enables anterograde integrin transport and increases integrin levels throughout the axon. Depletion of EFA6 promotes axon transport of Rab11, but not transport of amyloid precursor protein, which targets to CNS axons but is not normally found in Rab11 endosomes. Depleting EFA6 also enhances the regenerative ability of CNS axons. Finally, the authors show that ARF6 is regulated differently in CNS versus PNS neurons, suggesting that it is an intrinsic regulator of axon regeneration. These results describe a pivotal role of EFA6 in axonal regeneration, suggesting a new focus for research in this area and potential new therapeutic targets.
