Nerve injury signaling

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Although neurons within the peripheral nervous system (PNS) have a remarkable ability to repair themselves after injury, neurons within the central nervous system (CNS) do not spontaneously regenerate. This problem has remained recalcitrant despite a century of research on the reaction of axons to injury. The balance between inhibitory cues present in the environment and the intrinsic growth capacity of the injured neuron determines the extent of axonal regeneration following injury. The cell body of an injured neuron must receive accurate and timely information about the site and extent of axonal damage in order to increase its intrinsic growth capacity and successfully regenerate. One of the mechanisms contributing to this process is retrograde transport of injury signals. For example, molecules activated at the injury site convey information to the cell body leading to the expression of regeneration-associated genes and increased growth capacity of the neuron. Here we discuss recent studies that have begun to dissect the injury-signaling pathways involved in stimulating the intrinsic growth capacity of injured neurons.

Introduction

The extremely polarized morphology of neurons (i.e. axon length extending for up to 1 m) poses challenging problems for intracellular-signaling pathways. Information about distant injury, for example, has to be communicated to the cell body to initiate a proper regenerative response. Research on nerve regeneration has classically focused on identifying the inhibitory factors present in the environment, which include the glial scar and molecules such as Nogo and myelin-associated glycoprotein [1]. We know much less about the mechanisms that activate the intrinsic growth capacity of neurons following injury. Upon embryonic to adult transition, the intrinsic neuronal growth activity is repressed to allow for proper synaptic development. Injury to adult peripheral neurons, but not to central nervous system (CNS) neurons, reactivates the intrinsic growth capacity and allows regeneration to occur. Primary sensory neurons with cell bodies in the dorsal root ganglion (DRG) provide a useful model system to study the mechanisms that regulate regeneration. DRG neurons are pseudobipolar neurons and possess two axonal branches: a peripheral axon that regenerates when injured and a centrally projecting axon that does not regenerate following injury. Remarkably, injury to the peripheral branch before injury to the central branch promotes regeneration of central axons [2, 3]. This phenomenon is referred to as the ‘conditioning lesion’ paradigm (Figure 1) and indicates that retrograde injury signals travel from the peripheral injury site back to the cell body to increase the intrinsic growth capacity of the neuron. An increased intrinsic growth state as a result of a preconditioning lesion may enable centrally injured axons to regenerate. A series of elegant studies in the early 1990s in the mollusk Aplysia californica provided evidence for the existence of multiple injury signals functioning in a temporal sequence [4]: injury-induced discharge of axonal potentials, interruption of the normal supply of retrogradely transported target-derived factors (also called negative injury signals) and retrograde injury signals traveling from the injury site back to the cell body (also called positive injury signals) (Figure 2).

The retrograde transport of injury signals is one of the essential cellular mechanisms leading to regeneration. Coordination between several injury-signaling pathways is necessary to regulate the appropriate genes to promote neuronal survival and increase the intrinsic growth state of injured neurons. In this review, we discuss recent studies that departed from the traditional focus on extrinsic factors and uncovered distinct signaling mechanisms leading to the enhanced intrinsic growth capacity of peripheral neurons following injury.

Section snippets

Positive injury signals

The positive injury signals identified thus far cover a broad array of functionally distinct proteins that include members of the mitogen-activated protein kinase family (MAPK), cytokines, and their downstream transcription factors, as well as locally translated importin, a main regulator of nuclear import and export.

Axonal transport of several kinases was initially suggested to play a role in relaying information from the nerve terminal to the cell body [5]. It is now known that axonal injury

Role of cAMP

Elevation of cAMP levels in the soma following axonal injury to peripheral neurons contributes to the initiation of axonal regrowth (for a recent review, see [39]). cAMP not only increases the growth capacity of injured neurons but also partly relieves CNS myelin inhibition. The increase in cAMP levels appears to be transient and initiates a series of signaling pathways involving PKA [40]. The effects of cAMP are transcription dependent [41] and require the transcription factor cAMP response

Conclusions

A single signaling pathway is unlikely to fully mediate nerve regeneration. Several classes of injury signals may coexist to ensure precise information on the nature of the damage and its distance from the cell body (Figure 3). It is tempting to speculate that the difference in time between the arrival at the soma of the back propagating axonal depolarization  the first injury signal, and the later arrival of a positive injury signal might serve as an indicator of the distance of the injury site

References and recommended reading

Paper of particular interests, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Vitaly Klyachko and Erik Herzog for crucial reading of the manuscript. This work was supported by NIH (NS060709) to Valeria Cavalli.

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