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Intrinsic mechanisms of neuronal axon regeneration

Abstract

Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

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Fig. 1: Signalling events following peripheral axon injury.
Fig. 2: Model of epigenetic activation of pro-regenerative genes in response to axon injury.

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Acknowledgements

The authors’ research on these topics has been generously supported by the US National Institute of Health grants NS096034, NS082446 and NS099603, the University of Missouri Spinal Cord Injury Research Program and a Philip and Sima K. Needleman Doctoral Fellowship. The authors thank H. Gabel for helpful comments and critical reading of the manuscript. The authors thank the Cavalli laboratory members for their helpful comments on the manuscript. The authors apologize to those whose studies could not be cited owing to space limitation.

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Nature Reviews Neuroscience thanks S. Di Giovanni, J. Twiss and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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M.M. and V.C. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Valeria Cavalli.

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Glossary

Transcription factors

Proteins that activate or repress the expression of genes by binding to DNA sequence motifs proximal to a gene’s transcription start site or interacting enhancer regions.

Epigenetic modifiers

Proteins that post-translationally modify either DNA or histones, which affects DNA compaction and accessibility for protein binding.

MicroRNAs

(miRNAs). Single-stranded RNA molecules of 20–23 nucleotides in length, generated endogenously from a single-stranded hairpin precursor, which act as post-transcriptional inhibitors in association with the RNA-induced silencing complex (RISC).

Motor proteins

Proteins, such as kinesin, dynein and myosin, that use either the microtubule or the actin cytoskeleton for movement by converting chemical energy into mechanical force.

Cofactor

Protein that binds with other proteins to form heteromeric complexes that alter or enhance the function of its binding partners.

Poly(ADP-ribose)

A negatively charged polymer of ADP-ribose that can be added to proteins. Poly(ADP-ribose) represents a unique post-translational modification that regulates protein function.

RNA processing

The process by which an RNA molecule translated from DNA undergoes modifications, including 5′ capping, 3′ polyadenylation, splicing and methylation, before the RNA is translated into a protein.

Unfolded protein response

A cellular stress response that is triggered by an excess of unfolded or misfolded proteins in the endoplasmic reticulum.

Epitranscriptomic mechanisms

Post-transcriptional RNA modifications that regulate mRNA half-life or translation or otherwise alter biological processes.

Next-generation sequencing

High-throughput parallel sequencing of either DNA or RNA.

Cytokines

Originally defined as immune system proteins, these proteins are now known to be released by most cells and are important in regulating intercellular communication, cell function and cell survival.

Induced pluripotent stem cells

(iPSCs). Cells created from differentiated cell types (for example, fibroblasts) that are reprogrammed by a cocktail of transcription factors (or other approaches) back to a pluripotent state and are capable of differentiating into all three germ layers.

Genome topology

The 3D DNA structure that dictates its accessibility to binding by proteins such as transcription factors and epigenetic modifiers.

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Mahar, M., Cavalli, V. Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci 19, 323–337 (2018). https://doi.org/10.1038/s41583-018-0001-8

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