A mouse dorsal root ganglion explant showing neurite outgrowth that was stimulated by engagement of the Fas receptor. Reproduced, with permission, from Desbarats et al., Nature Cell Biology © (2003) Macmillan Magazines Ltd.

The regeneration of axons after peripheral nerve injury depends on the activation of signalling pathways that induce neurite sprouting from the damaged neurons. In Nature Cell Biology, Desbarats et al. show that a pivotal component of one such pathway is the Fas receptor, which is more commonly associated with cell death, and they also provide some intriguing insights into the molecular mechanisms that underlie Fas-mediated neurite growth.

Fas was initially identified in lymphocytes, in which crosslinking of Fas receptors by the Fas ligand (FasL) stimulates the cleavage of caspase 8. This initiates the caspase cascade, which culminates in apoptotic cell death. However, it is becoming increasingly clear that in other cellular contexts, including some neurons and glia, the engagement of Fas receptors by FasL or Fas-specific antibodies can have the opposite effect of stimulating growth.

Desbarats et al. examined the consequences of Fas engagement in two cell lines — a T-cell leukaemia line and a neuroblastoma line. They found that in the T cells, Fas engagement activated the caspase cascade, and the cells underwent apoptosis. In the neuroblastoma line, the outcome was different — caspase 8 was not cleaved and the cells did not die. Instead, the cells responded normally to the culture conditions by extending fine neurites, and they activated the extracellular-signal regulated kinase (ERK) cascade, which has previously been implicated in neurite outgrowth. By treating dorsal root ganglion explants with Fas crosslinking antibodies, the authors showed that Fas-mediated activation of the ERK cascade can promote neurite growth in primary sensory neurons.

Crucially, Desbarats et al. showed that Fas engagement also stimulates axon regeneration in vivo. In mice, they measured the time taken for functional recovery of a limb after a sciatic nerve crush injury, and they found that this process was delayed in a Fas-deficient mutant line. Conversely, injecting a Fas crosslinking antibody at the site of injury in wild-type mice accelerated their recovery. A mutation that only affected the death domain of the Fas receptor did not adversely affect functional recovery, implying that the pro-apoptotic activity of Fas is not required for axon regeneration.

It is still not clear what factors cause Fas to activate the ERK pathway rather than the caspase cascade, although it seems likely that the outcome of Fas engagement depends not only on the cell type, but also on the metabolic state of the cell. It is also interesting to note that the neurons that Desbarats et al. used in this study expressed very low levels of caspase 8. If the conditions that favour the activation of the ERK pathway over the caspase cascade can be identified, it might be possible to use this knowledge to develop new therapeutic approaches to treat nerve injury.