, 2005 and Liu et al., 2011). A key component of the injury signal is phosphorylated cJun N-terminal kinase (JNK) that activates the AP-1 transcription factor c-Jun required for axon regeneration (Raivich et al., 2004 and Cavalli et al., 2005). Axotomy of PNS neurons induces a local response in the proximal stump that repairs damage, activates a retrograde injury signal, and initiates a growth cone (Bradke et al., 2012). The initial outgrowth is often slow but accelerates after the retrograde injury signal activates the intrinsic regeneration program in the cell body (Figure 1). This is clearly seen with the preconditioning

paradigm in which growth cone initiation occurs selleck screening library with a shorter latency, and growth cone motility is significantly increased (McQuarrie and Grafstein, 1973). In the current paper, Shin et al. (2012) identified the dual leucine zipper kinase (DLK) as the molecule required for the retrograde transport of the injury signal activating the intrinsic regeneration program. DLK is a mitogen-activated protein kinase kinase kinase (MAPKKK) that has been shown to activate JNK and p38 MAPK. Previous work has demonstrated roles for DLK in

neural development BIBW2992 concentration as well as injury responses related to axon degeneration and apoptosis (Miller et al., 2009). The homologs of DLK in C. elegans and Drosophila have also been implicated in regenerative responses after axotomy ( Hammarlund et al., 2009, Yan et al., 2009, Ghosh-Roy et al., 2010, Nix et al., 2011, Xiong et al., 2010 and Xiong and Collins, 2012). Axon regeneration of both motor and sensory axons was severely delayed in the DLK knockout (KO) axons. Motor axon regeneration was assayed by scoring reinnervation of a hindlimb muscle after unilateral crush of the sciatic nerve. Wild-type axons

reinnervated about 80% of the muscle endplates, before while DLK KO axons reinnervated only 10% of the muscle endplates at 2 weeks postinjury. Sensory neuron regeneration was assayed by measuring the length of axons growing past the crush site 3 days postinjury. In this assay, the loss of DLK reduced growth of sensory neurons by about one half, although it was not possible to tell how much of the difference was due to delayed initiation of growth cones versus slower axon growth. In addition, with the aim of gaining insights into the mechanisms involved, Shin et al. (2012) also assayed the early phase of axonal regrowth 1 day postcrush and found there was no difference in axon outgrowth, suggesting that the difference in regeneration seen in DLK KO axon is due to slower migration of growth cones. Looking more closely at growth cone formation by assaying regeneration in cultured dorsal root ganglion (DRG) neurons, they found that the ratio of severed axons that form growth cones within 2 hr of axotomy was not significantly different between wild-type and DLK KO axons.