1. Neuroscience
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Selective Rab11 transport and the intrinsic regenerative ability of CNS axons

  1. Hiroaki Koseki
  2. Matteo Donegá
  3. Brian YH Lam
  4. Veselina Petrova
  5. Susan van Erp
  6. Giles SH Yeo
  7. Jessica CF Kwok
  8. Charles ffrench-Constant
  9. RIchard Eva  Is a corresponding author
  10. James Fawcett  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Edinburgh, United Kingdom
  3. University of Leeds, United Kingdom
Research Article
  • Cited 32
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Cite this article as: eLife 2017;6:e26956 doi: 10.7554/eLife.26956

Abstract

Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity Rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons. Their transport changed from bidirectional to retrograde. However, on overexpression Rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration.

Data availability

The following data sets were generated
    1. Lam B
    2. Koseki H
    (2016) Maturation of cortical neurons
    Publicly available at NCBI Gene Expression Omnibus (accession no: GSE92856).

Article and author information

Author details

  1. Hiroaki Koseki

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Matteo Donegá

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Brian YH Lam

    Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Veselina Petrova

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Susan van Erp

    MRC Centre of Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0883-2795
  6. Giles SH Yeo

    Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jessica CF Kwok

    School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Charles ffrench-Constant

    MRC Centre for Regenerative Medicine, Centre for Multiple Sclerosis Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. RIchard Eva

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    re263@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  10. James Fawcett

    John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    jf108@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7990-4568

Funding

Medical Research Council (G1000864)

  • James Fawcett

Christopher and Dana Reeve Foundation (International Consortium)

  • James Fawcett

European Research Council (ECMneuro)

  • James Fawcett

GlaxoSmithKline International Scholarship

  • Hiroaki Koseki

Honjo International Scholarship Foundation

  • Hiroaki Koseki

Bristol Myers Squibb Graduate Studentship

  • Hiroaki Koseki

National Institute of Health Research (Cambridge Biomedical Research Centre)

  • James Fawcett

Czech ministry of education (CZ.02.1.01/0.0./0.0/15_003/0000419)

  • Jessica CF Kwok
  • James Fawcett

European Molecular Biology Organization (Long Term EMBO Fellowship (ALTF 1436-2015))

  • Susan van Erp

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Publication history

  1. Received: March 18, 2017
  2. Accepted: August 7, 2017
  3. Accepted Manuscript published: August 8, 2017 (version 1)
  4. Accepted Manuscript updated: August 10, 2017 (version 2)
  5. Accepted Manuscript updated: August 30, 2017 (version 3)
  6. Version of Record published: September 22, 2017 (version 4)

Copyright

© 2017, Koseki et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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