However, these results support the hypothesis that DLK is required for improved growth cone performance subsequent to activation of the intrinsic regeneration program at the cell body, but not for the locally regulated initiation

and extension of the growth cone. Is DLK DAPT mw the signaling molecule responsible for the improved axon regeneration induced by a preconditioning injury? Wild-type sensory axons respond to a preconditioning injury with an accelerated regeneration after a second injury (McQuarrie and Grafstein, 1973 and Hoffman, 2010). Shin et al. (2012) found that this conditioning injury effect was completely abolished in DLK KO sciatic sensory axons in vivo. The sciatic nerve was crushed, 3 days later a second crush was

made, and 1 day later axon growth was measured. Wild-type axons respond with a 2-fold increase in the “index” of regeneration, but the DLK KO axons showed no increase. They also examined the direct effect on growth cone extension in cultured DRG neurons by crushing the sciatic nerve, waiting 3 days, and then culturing the preconditioned cells. After 16 hr in culture, the wild-type axons showed the expected accelerated growth, but this effect was absent in the DLK KO axons. The loss of DLK abolished any response to a preconditioning injury (Figure 1). The only preconditioning see more effect not mimicked by DLK seems to be the shortened latency to growth cone formation, but Shin et al. (2012) did not directly address whether there was a change in latency after a preconditioning injury in their experiments (Hoffman, 2010). Next, Shin et al. (2012) wanted to identify the molecular signals regulated by DLK and responsible for the retrograde activation of the cell-intrinsic regeneration program. As expected, they identified the known DLK/JNK target c-Jun (Raivich et al., 2004). Phosphorylated c-Jun was assayed

in the DRG cell nuclei in response to sciatic nerve second crush and found to be completely blocked in the DLK KO cells. However, phosphorylated STAT3 is absent from DRG cell bodies after nerve crush in DLK KO cells. The level of phosphorylated STAT3 in crushed axons was unchanged in the DLK KO, suggesting that DLK might regulate its retrograde transport. They tested this model with a double ligation experiment and found that the retrograde transport of p-STAT, in addition to JIP3 and p-JNK, depends on DLK function. These results support a model in which DLK is the local axon injury sensor that functions to regulate the retrograde transport of signaling molecules activating the cell-intrinsic regeneration program (Cavalli et al., 2005). There are some surprising similarities between DLK function in mouse and C. elegans axon regeneration.