Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
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
-
Maturation of cortical neuronsPublicly available at NCBI Gene Expression Omnibus (accession no: GSE92856).
Article and author information
Author details
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
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India
Version history
- Received: March 18, 2017
- Accepted: August 7, 2017
- Accepted Manuscript published: August 8, 2017 (version 1)
- Accepted Manuscript updated: August 10, 2017 (version 2)
- Accepted Manuscript updated: August 30, 2017 (version 3)
- 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.
Metrics
-
- 3,562
- views
-
- 626
- downloads
-
- 57
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Neuroscience
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
-
- Neuroscience
We are unresponsive during slow-wave sleep but continue monitoring external events for survival. Our brain wakens us when danger is imminent. If events are non-threatening, our brain might store them for later consideration to improve decision-making. To test this hypothesis, we examined whether novel vocabulary consisting of simultaneously played pseudowords and translation words are encoded/stored during sleep, and which neural-electrical events facilitate encoding/storage. An algorithm for brain-state-dependent stimulation selectively targeted word pairs to slow-wave peaks or troughs. Retrieval tests were given 12 and 36 hr later. These tests required decisions regarding the semantic category of previously sleep-played pseudowords. The sleep-played vocabulary influenced awake decision-making 36 hr later, if targeted to troughs. The words’ linguistic processing raised neural complexity. The words’ semantic-associative encoding was supported by increased theta power during the ensuing peak. Fast-spindle power ramped up during a second peak likely aiding consolidation. Hence, new vocabulary played during slow-wave sleep was stored and influenced decision-making days later.