Abstract
Mammalian neurons lose the ability to regenerate their central nervous system axons as they mature during embryonic or early postnatal development. Neuronal maturation requires a transformation from a situation in which neuronal components grow and assemble to one in which these components are fixed and involved in the machinery for effective information transmission and computation. To regenerate after injury, neurons need to overcome this fixed state to reactivate their growth programme. A variety of intracellular processes involved in initiating or sustaining neuronal maturation, including the regulation of gene expression, cytoskeletal restructuring and shifts in intracellular trafficking, have been shown to prevent axon regeneration. Understanding these processes will contribute to the identification of targets to promote repair after injury or disease.
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Acknowledgements
B.J.H. is supported by the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986), the Canadian Foundation for Innovation, and the Michael Smith Foundation for Health Research BC. This work was supported by Deutsche Forschungsgesellschaft (DFG), the International Foundation for Research in Paraplegia (IRP) and Wings for Life (to F.B). F.B. is a member of the excellence cluster ImmunoSensation2, the SFBs 1089 and 1158, and is a recipient of the Roger De Spoelberch Prize. We also thank P. Scheiffele for discussions.
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B.J.H., J.W.F., J.M.G. and F.B. researched data for the article. B.J.H., J.W.F and F.B. wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.
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Glossary
- Active zone
-
The section of the presynaptic plasma membrane within which synaptic vesicle exocytosis takes place.
- Autophagosome
-
A double-membraned vesicle that is formed during autophagy and engulfs and degrades intracellular material.
- Axon initial segment
-
(AIS). The region of the axon close to the soma. The AIS is responsible for the generation of action potentials and demarcates the boundary between axonal and somatodendritic compartments of the neuron.
- Cell adhesion molecules
-
Proteins located on the surface of the cell that mediate interactions between cells or between cells and the extracellular matrix.
- Chromatin
-
The combination of DNA and histone proteins that together comprise chromosomes.
- Cytoskeletal dynamics
-
The interactions between cytoskeletal filaments and accessory proteins that dictate cytoskeletal assembly, disassembly and function.
- Differentiation
-
The process through which immature and less specialized cells acquire structural and functional specificity.
- Endosomes
-
Membrane-bound vesicles that have a role in intracellular sorting in eukaryotic cells.
- Enhancers
-
Sequences of DNA that are located in proximity to a gene and that can be bound by proteins to enhance the likelihood of that gene’s transcription.
- Epigenetic mechanisms
-
Processes that regulate gene expression without changing the DNA sequence.
- Extracellular matrix
-
The network of extracellular molecules that provide structural and biochemical support to cells.
- Growth cone
-
A specialized and motile structure found at the distal tip of a growing neurite.
- Local translation
-
Synthesis of proteins at a specialized site within the cell, such as the axon, dendrite, or synapse.
- Microtubule
-
A polymer of tubulin that is a major part of the cytoskeleton.
- Nucleosomes
-
Segments of DNA wound around histone proteins, constituting the fundamental organization of DNA packaging and resembling ‘beads on a string’.
- Promoters
-
Sequences of DNA to which proteins can bind in order to initiate the transcription of RNA.
- Regeneration-associated genes
-
(RAGs). A historical term in the axon regeneration field referring to genes with expression profiles that positively correlate with axon growth competence, such as those upregulated after peripheral nerve injury.
- Retrograde injury signalling
-
The process by which the neuron signals from its injured axon back to its nucleus to orchestrate the cell body’s response to injury.
- Transcytosis
-
A type of specialized transport in which molecules and/or cargo are taken into a vesicle, transported to a different area of the cell and then secreted.
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Hilton, B.J., Griffin, J.M., Fawcett, J.W. et al. Neuronal maturation and axon regeneration: unfixing circuitry to enable repair. Nat. Rev. Neurosci. 25, 649–667 (2024). https://doi.org/10.1038/s41583-024-00849-3
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DOI: https://doi.org/10.1038/s41583-024-00849-3