DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4039-44. doi: 10.1073/pnas.1211074110. Epub 2013 Feb 19.


The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Axons / pathology
  • Axons / physiology*
  • MAP Kinase Kinase Kinases / deficiency
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Nerve Regeneration / genetics
  • Nerve Regeneration / physiology*
  • Optic Nerve Injuries / genetics
  • Optic Nerve Injuries / pathology
  • Optic Nerve Injuries / physiopathology
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology
  • Retinal Ganglion Cells / pathology
  • Retinal Ganglion Cells / physiology
  • Transcription, Genetic


  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 12
  • PTEN Phosphohydrolase
  • Pten protein, mouse