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 by predominant retrograde transport 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.

Centre of Reconstructive Neuroscience Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom

John van Geest Centre for Brain Repair University of Cambridge Cambridge United Kingdom

MRC Centre of Regenerative Medicine University of Edinburgh Edinburgh United Kingdom

MRC Metabolic Diseases Unit Metabolic Research Laboratories University of Cambridge Cambridge United Kingdom

School of Biomedical Sciences Faculty of Biological Sciences University of Leeds Leeds United Kingdom

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Hyperactive delta isoform of PI3 kinase enables long-distance regeneration of adult rat corticospinal tract

Neuronal maturation and axon regeneration: unfixing circuitry to enable repair

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Long-Term Cultures of Spinal Cord Interneurons

Age-related loss of axonal regeneration is reflected by the level of local translation

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters

Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Integrins promote axonal regeneration after injury of the nervous system

EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment