c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

Brain. 2014 Nov;137(Pt 11):2922-37. doi: 10.1093/brain/awu257. Epub 2014 Sep 12.


Charcot-Marie-Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot-Marie-Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot-Marie-Tooth disease type 1A. In line with our previous findings in humans with Charcot-Marie-Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun(-/-) mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot-Marie-Tooth disease type 1A: on the one hand they are the genetic source of the disease, on the other, they respond to it by mounting a c-Jun-dependent response that significantly reduces its impact. Because axonal death is a central feature of much nerve pathology it will be important to establish whether an axon-supportive Schwann cell response also takes place in other conditions. Amplification of this axon-supportive mechanism constitutes a novel target for clinical intervention that might be useful in Charcot-Marie-Tooth disease type 1A and other neuropathies that involve axon loss.

Keywords: axonal degeneration; demyelinating disease; neural repair; neuron-glial interaction; neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Behavior, Animal / physiology
  • Charcot-Marie-Tooth Disease / metabolism*
  • Charcot-Marie-Tooth Disease / physiopathology
  • Demyelinating Diseases / metabolism*
  • Demyelinating Diseases / pathology
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Schwann Cells / metabolism*


  • Proto-Oncogene Proteins c-jun