Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury

Abstract

Nerve injury can lead to axonal regeneration, axonal degeneration, and/or neuronal cell death. Remarkably, the MAP3K dual leucine zipper kinase, DLK, promotes each of these responses, suggesting that DLK is a sensor of axon injury. In Drosophila, mutations in proteins that stabilize the actin and microtubule cytoskeletons activate the DLK pathway, suggesting that DLK may be activated by cytoskeletal disruption. Here we test this model in mammalian sensory neurons. We find that pharmacological agents designed to disrupt either the actin or microtubule cytoskeleton activate the DLK pathway, and that activation is independent of calcium influx or induction of the axon degeneration program. Moreover, activation of the DLK pathway by targeting the cytoskeleton induces a pro-regenerative state, enhancing axon regeneration in response to a subsequent injury in a process akin to preconditioning. This highlights the potential utility of activating the DLK pathway as a method to improve axon regeneration. Moreover, DLK is required for these responses to cytoskeletal perturbations, suggesting that DLK functions as a key neuronal sensor of cytoskeletal damage.

Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction

“…Because axonal injury activates both MTORC1 and DLK/JNK (Abe et al, 2010; Kenney and Kocsis, 1998; Valakh et al, 2015), our findings imply a functional connection between these two pathways. Interestingly, our data also suggest that MTORC1 contains additional kinases besides MTOR that can phosphorylate Wnd.…”

Novel DLK-independent neuronal regeneration in Caenorhabditis elegans shares links with activity-dependent ectopic outgrowth

“…Importantly, DLK-independent and lesion-conditioned regeneration also exhibit a similar regeneration phenotype dependent on the sequence and timing of neurite lesions, including a preconditioning effect. In mammals, DLK underlies preconditioning of peripheral axon regeneration (21), a conditioning effect on DRG neurons in vitro (43), and retinal ganglion cell regeneration after optic nerve crush (44). Nonetheless, the similarities with the C. elegans DLKindependent regeneration observed here suggest the possibility of modeling aspects of CNS lesion conditioning in genetically accessible systems.…”

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

“…One intriguing candidate is cytoskeletal disruption. In worms, flies, and mice, genetic and/or pharmacological manipulations that impair normal cytoskeletal function activate DLK (Bounoutas et al, 2011; Marcette et al, 2014; Valakh et al, 2013, 2015). Cytoskeletal disruption occurs in traumatic axon injury and in response to neurotoxic chemotherapeutics such as vincristine and taxol that cause neuropathy, and so is well positioned to serve as an injury signal.…”