Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
- University of Cambridge, United Kingdom
- University of Edinburgh, United Kingdom
- University of Leeds, United Kingdom
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
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
- 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
-
- 3,606
- views
-
- 632
- downloads
-
- 57
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
eLife 6:e26956.
https://doi.org/10.7554/eLife.26956
Further reading
-
- Neuroscience
Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.
-
- Neuroscience
Acetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.
