Exclusion of integrins from CNS axons is regulated by the axon initial segment and Arf6 activation.
Franssen, Elske HP
Hoogenraad, Casper C
Journal of Neuroscience
Society for Neuroscience
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Franssen, E. H., Zhao, R., Koseki, H., Venkateswarlu, K., Hoogenraad, C. C., Eva, R., & Fawcett, J. (2015). Exclusion of integrins from CNS axons is regulated by the axon initial segment and Arf6 activation.. Journal of Neuroscience, 35 8359-8375. https://doi.org/10.1523/JNEUROSCI.2850-14.2015
Integrins are adhesion and survival molecules involved in axon growth during central nervous system (CNS) development as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in this paper we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs, and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons but not dendrites as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons and increases axon growth. Additionally we found that the axon initial segment (AIS) is partly responsible for exclusion of integrins; removal of this structure allows integrins into axons. Changing post-translational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking.
Axonal transport, integrin, trafficking, Arf6, axon initial segment
The authors thank Dr. Matthew N. Rasband for kindly providing the adenoviruses for ankG silencing experiment and Dr. Juan Bonifacino for AP-1 constructs. We also thank Menghon Cheah for his assistance. We acknowledge funding from the Medical Research Council, the Christopher and Dana Reeve Foundation, EU Framework 7 Project Plasticise, the European Research Council, the John and Lucille van Geest Foundation, and the NIHR Cambridge Biomedical Research Centre.
MEDICAL RESEARCH COUNCIL (G1000864)
External DOI: https://doi.org/10.1523/JNEUROSCI.2850-14.2015
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247899
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/