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
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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.
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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Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
eLife 6:e26956.
https://doi.org/10.7554/eLife.26956
Further reading
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- Neuroscience
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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- Neuroscience
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
