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

Neurobiol Dis. 2015 May;77:13-25. doi: 10.1016/j.nbd.2015.02.014. Epub 2015 Feb 26.

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.

Keywords: Axon regrowth; Cytoskeleton; DLK; DRG; Neuron; Neuropathy; Regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium-Binding Proteins
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Cytochalasin D / pharmacology
  • Cytoskeleton / metabolism
  • Embryo, Mammalian
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Ganglia, Spinal / cytology
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / genetics
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Nocodazole / pharmacology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Time Factors

Substances

  • Calcium-Binding Proteins
  • Chelating Agents
  • Dlk1 protein, mouse
  • Enzyme Inhibitors
  • Intercellular Signaling Peptides and Proteins
  • Cytochalasin D
  • MAP Kinase Kinase 4
  • Nocodazole