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EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment

Richard Eva, Hiroaki Koseki, Venkat Kanamarlapudi Orcid Logo, James W. Fawcett

Journal of Cell Science, Volume: 130, Issue: 21, Pages: 3663 - 3675

Swansea University Author: Venkat Kanamarlapudi Orcid Logo

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DOI (Published version): 10.1242/jcs.207423

Abstract

Central nervous system (CNS) axons lose their intrinsic ability to regenerate with maturity, whilst peripheral (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...

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Published in: Journal of Cell Science
ISSN: 0021-9533 1477-9137
Published: 2017
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URI: https://cronfa.swan.ac.uk/Record/cronfa35637
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first_indexed 2017-09-26T04:12:43Z
last_indexed 2020-07-14T18:56:06Z
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spelling 2020-07-14T14:38:25.0072135 v2 35637 2017-09-25 EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2017-09-25 BMS Central nervous system (CNS) axons lose their intrinsic ability to regenerate with maturity, whilst peripheral (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 using laser axotomy. We identify a novel regulator of selective axon transport and regeneration, the ARF6 GEF EFA6. EFA6 exerts its effects from a location within the axon initial segment (AIS). EFA6 does not localise here in DRG axons, and in these neurons, ARF activation is counteracted by an ARF-GAP which is absent from the CNS, ACAP1. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances regeneration, whilst 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 axon initial segment, signalling and transport. Journal Article Journal of Cell Science 130 21 3663 3675 0021-9533 1477-9137 Axon initial segment; Axon regeneration; Axon transport; Integrins; Neuronal polarisation; Recycling endosomes 1 11 2017 2017-11-01 10.1242/jcs.207423 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCUK 2020-07-14T14:38:25.0072135 2017-09-25T20:35:30.5473989 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Richard Eva 1 Hiroaki Koseki 2 Venkat Kanamarlapudi 0000-0002-8739-1483 3 James W. Fawcett 4 0035637-06112017174425.pdf EFA6polartransportaxonalregenJCS17.pdf 2017-11-06T17:44:25.4400000 Output 9428378 application/pdf Version of Record true 2017-11-06T00:00:00.0000000 This is an open access article distributed under CC BY licence. true eng
title EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
spellingShingle EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
Venkat Kanamarlapudi
title_short EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
title_full EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
title_fullStr EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
title_full_unstemmed EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
title_sort EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Venkat Kanamarlapudi
author2 Richard Eva
Hiroaki Koseki
Venkat Kanamarlapudi
James W. Fawcett
format Journal article
container_title Journal of Cell Science
container_volume 130
container_issue 21
container_start_page 3663
publishDate 2017
institution Swansea University
issn 0021-9533
1477-9137
doi_str_mv 10.1242/jcs.207423
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Central nervous system (CNS) axons lose their intrinsic ability to regenerate with maturity, whilst peripheral (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 using laser axotomy. We identify a novel regulator of selective axon transport and regeneration, the ARF6 GEF EFA6. EFA6 exerts its effects from a location within the axon initial segment (AIS). EFA6 does not localise here in DRG axons, and in these neurons, ARF activation is counteracted by an ARF-GAP which is absent from the CNS, ACAP1. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances regeneration, whilst 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 axon initial segment, signalling and transport.
published_date 2017-11-01T03:44:24Z
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score 11.013619

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