EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
Journal of Cell Science
The Company of Biologists Ltd.
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Eva, R., Koseki, H., Kanamarlapudi, V., & Fawcett, J. (2017). EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment. Journal of Cell Science, 130 3663-3675. https://doi.org/10.1242/jcs.207423
Central nervous system (CNS) axons lose their intrinsic ability to regenerate upon maturity, whereas peripheral nervous system (PNS) axons do not. A key difference between these neuronal types is their ability to transport integrins into axons. Integrins can mediate PNS regeneration, but are excluded from adult CNS axons along with their Rab11 carriers. We reasoned that exclusion of the contents of Rab11 vesicles including integrins might contribute to the intrinsic inability of CNS neurons to regenerate, and investigated this by performing laser axotomy. We identify a novel regulator of selective axon transport and regeneration, the ARF6 guanine-nucleotide-exchange factor (GEF) EFA6 (also known as PSD). EFA6 exerts its effects from a location within the axon initial segment (AIS). EFA6 does not localise at the AIS in dorsal root ganglion (DRG) axons, and in these neurons, ARF6 activation is counteracted by an ARF GTPase-activating protein (GAP), which is absent from the CNS, ACAP1. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances regeneration, whereas overexpressing EFA6 prevents DRG regeneration. Our results demonstrate that ARF6 is an intrinsic regulator of regenerative capacity, implicating EFA6 as a focal molecule linking the AIS, signalling and transport.
axon regeneration, axon transport, neuronal polarisation, axon initial segment, integrins, recycling endosomes
The study was funded by grants from the Christopher and Dana Reeve Foundation, the Medical Research Council, the ERC advanced grant ECMneuro, the International Spinal Research Trust, Glaxo Smith Kline International Scholarship, Honjo International Scholarship, Bristol-Myers Squibb Graduate Studentship and the NIHR Cambridge Biomedical Research Centre.
MEDICAL RESEARCH COUNCIL (G1000864)
External DOI: https://doi.org/10.1242/jcs.207423
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268138
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