DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury

Neurobiol Dis. 2014 Sep;69:108-16. doi: 10.1016/j.nbd.2014.05.015. Epub 2014 May 27.

Abstract

Injury to retinal ganglion cell (RGC) axons triggers rapid activation of Jun N-terminal kinase (JNK) signaling, a major prodeath pathway in injured RGCs. Of the multiple kinases that can activate JNK, dual leucine kinase (Dlk) is known to regulate both apoptosis and Wallerian degeneration triggered by axonal insult. Here we tested the importance of Dlk in regulating somal and axonal degeneration of RGCs following axonal injury. Removal of DLK from the developing optic cup did not grossly affect developmental RGC death or inner plexiform layer organization. In the adult, Dlk deficiency significantly delayed axonal-injury induced RGC death. The activation of JUN was also attenuated in Dlk deficient retinas. Dlk deficiency attenuated the activation of the somal pool of JNK but did not prevent activation of the axonal pool of JNK after axonal injury, indicating that JNK activation in different cellular compartments of an RGC following axonal injury is regulated by distinct upstream kinases. In contrast to its robust influence on somal degeneration, Dlk deficiency did not alter RGC axonal degeneration after axonal injury as assessed using physiological readouts of optic nerve function.

Keywords: Axonopathy; Cell death; DLK; Glaucoma; MAPK; Wlds; cJUN.

Publication types

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

MeSH terms

  • Animals
  • Axons / enzymology*
  • Axons / pathology
  • Cell Death / physiology
  • Cell Survival / physiology
  • Disease Models, Animal
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinases / deficiency*
  • MAP Kinase Kinase Kinases / genetics
  • Mice, Transgenic
  • Optic Nerve Injuries / enzymology*
  • Optic Nerve Injuries / pathology
  • Phosphorylation / physiology
  • Retina / enzymology
  • Retina / growth & development
  • Retina / pathology
  • Retinal Ganglion Cells / enzymology*
  • Retinal Ganglion Cells / pathology
  • Signal Transduction
  • Tissue Culture Techniques
  • Wallerian Degeneration / enzymology*
  • Wallerian Degeneration / pathology

Substances

  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 12