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Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

E. H. P. Franssen, R.-R. Zhao, H. Koseki, V. Kanamarlapudi, C. C. Hoogenraad, R. Eva, J. W. Fawcett, Venkat Kanamarlapudi Orcid Logo

Journal of Neuroscience, Volume: 35, Issue: 21, Pages: 8359 - 8375

Swansea University Author: Venkat Kanamarlapudi Orcid Logo

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DOI (Published version): 10.1523/JNEUROSCI.2850-14.2015

Abstract

Integrins are adhesion and survival molecules involved in axon growth duringCNSdevelopment, 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 r...

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Published in: Journal of Neuroscience
ISSN: 0270-6474 1529-2401
Published: 2015
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URI: https://cronfa.swan.ac.uk/Record/cronfa21767
first_indexed 2015-05-29T02:08:33Z
last_indexed 2019-06-05T09:52:33Z
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spelling 2019-06-03T10:18:49.5872203 v2 21767 2015-05-28 Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2015-05-28 MEDS Integrins are adhesion and survival molecules involved in axon growth duringCNSdevelopment, 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 the present study, 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. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational 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. Journal Article Journal of Neuroscience 35 21 8359 8375 0270-6474 1529-2401 Arf6; axon initial segment; axonal transport; integrin; trafficking 27 5 2015 2015-05-27 10.1523/JNEUROSCI.2850-14.2015 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2019-06-03T10:18:49.5872203 2015-05-28T10:10:37.8251002 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine E. H. P. Franssen 1 R.-R. Zhao 2 H. Koseki 3 V. Kanamarlapudi 4 C. C. Hoogenraad 5 R. Eva 6 J. W. Fawcett 7 Venkat Kanamarlapudi 0000-0002-8739-1483 8 0021767-03062019101743.pdf 21767.pdf 2019-06-03T10:17:43.2900000 Output 34504122 application/pdf Version of Record true 2019-06-02T00:00:00.0000000 Released under the terms of a Creative Commons Attribution License (CC-BY). true eng
title Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
spellingShingle Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
Venkat Kanamarlapudi
title_short Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
title_full Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
title_fullStr Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
title_full_unstemmed Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
title_sort Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Venkat Kanamarlapudi
author2 E. H. P. Franssen
R.-R. Zhao
H. Koseki
V. Kanamarlapudi
C. C. Hoogenraad
R. Eva
J. W. Fawcett
Venkat Kanamarlapudi
format Journal article
container_title Journal of Neuroscience
container_volume 35
container_issue 21
container_start_page 8359
publishDate 2015
institution Swansea University
issn 0270-6474
1529-2401
doi_str_mv 10.1523/JNEUROSCI.2850-14.2015
college_str Faculty of Medicine, Health and Life Sciences
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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
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description Integrins are adhesion and survival molecules involved in axon growth duringCNSdevelopment, 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 the present study, 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. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational 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.
published_date 2015-05-27T06:42:45Z
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