Interestingly, the application of DAPT two hours

after axotomy failed to affect regeneration, suggesting that the inhibitory Notch activity is fairly rapidly triggered upon injury. A key issue to be addressed in future studies is how multiple intrinsic signaling events are activated upon injury and interact with each other to determine the injury response (Figure 1). Both inhibitory factors for regeneration, EFA-6 and Notch/LIN-12, are most effective during a narrow time window immediately following axotomy. Similarly, regeneration-promoting DLK-1 signaling is most critically required within two hours of the injury to enable growth cone initiation (Hammarlund et al., 2009). LBH589 Upstream regulators of EFA-6 remain elusive, but signals stemming from the site of injury, such as calcium influx and an increase of cAMP, probably play a role in DLK-1 activation (Ghosh-Roy et al., 2010). In the case of Notch signaling, no single known Notch ligand was found necessary to inhibit axon regeneration (El Bejjani and Hammarlund, 2012). One ligand DSL/LAG-2 even mildly promotes regrowth (El Bejjani and Hammarlund, 2012). It is possible that multiple ligands function

redundantly upon injury to activate Notch (Figure 1). These observations, however, also support a tantalizing possibility that axotomy itself is a shared trigger for multiple signaling responses, Selleckchem Ibrutinib including the activation of Notch processing independently of its canonical ligands. Despite a similar temporal requirement, DLK-1, EFA-6, and Notch signaling do not exhibit unequivocal linear genetic interactions. In efa-6; dlk-1 double mutants, severed PLM axons extend significantly longer than in dlk-1 mutants,

yet they failed to form growth cone-like structures ( Chen et al., 2011). The loss of Notch signaling could not bypass the requirement of DLK-1 to reinitiate growth cones in GABAergic neurons ( Ribonucleotide reductase El Bejjani and Hammarlund, 2012), arguing against a simplistic view where DLK-1 initiates axon regeneration by suppressing inhibitory signals from EFA-6 or Notch. While the genetic interactions between the Notch signaling and EFA-6 remain to be determined, an interplay of multiple, parallel signaling events may determine the injury response in individual neurons. These studies reinforce a notion that both common and specific factors contribute to the regeneration of different neurons. DLK-1 activity is necessary for the regrowth of both GABAergic motor neurons and PLM mechanosensory neurons. Whether EFA-6, an inhibitor of PLM axon regeneration, also affects the regeneration in GABAergic motor neurons remains to be tested. Whether Notch signaling significantly affects PLM regrowth requires more thorough investigation (Chen et al., 2011). However, as observed for Notch signaling components (El Bejjani and Hammarlund, 2012), some factors that regulate regeneration are probably cell type specific or are expressed at different levels in neuronal subtypes.