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  • Review Article
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Axon–soma communication in neuronal injury

Key Points

  • Neurons require specialized mechanisms of motor-facilitated signal transport for communication along long axonal distances to the cell body and the nucleus.

  • Recent evidence suggests that the early calcium wave elicited by an axonal injury induces epigenetic changes in the nucleus, thereby priming the system for subsequent transcriptional events.

  • JUN amino-terminal kinases (JNKs) and associated scaffolding and activator molecules participate in retrograde injury signalling. As JNK signalling can have effects that range from neurite growth promotion to cell death induction, multiple regulatory mechanisms are required to ensure specificity of the signal.

  • Importins associated with dynein are an important component of retrograde injury signalling complexes and enable transport of direct importin cargoes, such as transcription factors, as well as secondary cargoes that bind scaffolding molecules associated with importins.

  • Local translation of axonally localized mRNAs is required for retrograde injury signalling, enabling recruitment of key molecules such as importin β1 to the complex.

  • Combinatorial signalling and/or temporal or frequency-encoded signalling could be used to assess the injury location and extent of damage.

  • The emerging picture of a combinatorial signalling system that conveys both spatial and temporal information will help to guide future translational efforts.

Abstract

The extensive lengths of neuronal processes necessitate efficient mechanisms for communication with the cell body. Neuronal regeneration after nerve injury requires new transcription; thus, long-distance retrograde signalling from axonal lesion sites to the soma and nucleus is required. In recent years, considerable progress has been made in elucidating the mechanistic basis of this system. This has included the discovery of a priming role for early calcium waves; confirmation of central roles for mitogen-activated protein kinase signalling effectors, the importin family of nucleocytoplasmic transport factors and molecular motors such as dynein; and demonstration of the importance of local translation as a key regulatory mechanism. These recent findings provide a coherent mechanistic framework for axon–soma communication in the injured nerve and shed light on the integration of cytoplasmic and nuclear transport in all eukaryotic cells.

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Figure 1: Early events in axon–soma communication after nerve injury.
Figure 2: Retrograde signalling via the JUN kinase pathway after an axonal lesion.
Figure 3: Importins and local translation in retrograde injury signalling.
Figure 4: Lesion location and distance encoding by motor-dependent signalling.

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Acknowledgements

Our research on these topics has been generously supported by the European Research Council, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Israel Science Foundation, the USA-Israel Binational Science Foundation, the International Foundation for Research in Paraplegia, the Christopher & Dana Reeve Foundation and the Wings for Life Spinal Cord Research Foundation.

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Glossary

Calcium wave

A localized increase in intracellular calcium concentration that is propagated spatially along the neurite or through the cell body.

Growth cone

A dynamic motile extension at the tip of a growing neurite that senses molecular cues in the extracellular environment and leads axonal growth.

Immediate-early genes

Genes that are very rapidly induced upon an appropriate stimulation of the cell without any prior need for new protein synthesis.

Importins

A family of proteins that transport macromolecular cargoes through the nuclear pore complex into the nucleus.

Nuclear localization signal

(NLS). A short motif of basic amino acids in a cargo protein that binds to an importin, thus enabling nuclear import of the cargo protein.

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Rishal, I., Fainzilber, M. Axon–soma communication in neuronal injury. Nat Rev Neurosci 15, 32–42 (2014). https://doi.org/10.1038/nrn3609

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