Nerve injury signaling

Abstract

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.

Figure 1. Signalling mechanisms

The cell body of injured neurons must receive accurate and timely information on the site and extent of axonal damage in order to orchestrate an appropriate response leading to successful regeneration. Pioneering work from the laboratories of Ambron and Walters have led to the notion that three distinct signaling mechanisms may act in complementary and synergistic roles: (1) injury-induced discharge of axonal potentials, (2) interruption of the normal supply of retrogradely transported trophic factors or negative regulators of neuronal growth from the target and (3) retrograde transport of activated proteins emanating at the injury site, termed positive injury signals.

Figure 2. Conditioning injury paradigm

Primary sensory neurons within dorsal root ganglia (DRG) are particularly useful to study axonal regeneration. DRG neurons are unique in having two axonal branches; a long sensory CNS branch ascends the dorsal column in the spinal cord and a second branch projects through a peripheral nerve. Sensory axons in the adult spinal cord do not regenerate after injury (A), while peripheral injury result in a robust regenerative response. Regeneration of the central branch can be greatly enhanced by a prior injury to the peripheral branch, referred to as a “conditioning injury” (B). The conditioning injury suggests that distinct signaling mechanisms regulate responses to central vs. peripheral injury in DRG neurons and may contribute to their different abilities to axonal regrowth.

Figure 3. Activation of the intrinsic growth capacity by peripheral injury

Nerve injury triggers multiple signalling events in the axon, including membrane depolarization, JNK activation, mRNA translation, and cytokine-mediated STAT3 activation. These events lead to the microtubule-based retrograde transport of signaling molecules back to the cell body (shown by plain arrows). When these signalling molecules reach the cell body, they mediate the expression of a number of transcription factors that regulate the expression of genes involved in cell survival and neurite outgrowth. These downstream targets also include some components of the injury signal, such as IL-6 and LIF, which may amplify the injury signal via positive feedback.