title: c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy.
abstract: 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.
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Carty
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Wagstaff
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Turmaine
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Wilton
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Quintes
authors.affiliation: 2 UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Koltzenburg
authors.affiliation: 3 Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK.
authors.forename: Rhona
authors.initials: R
authors.lastname: Mirsky
authors.affiliation: 1 Department of Cell and Developmental Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK k.jessen@ucl.ac.uk.
authors.forename: Kristján R
authors.initials: KR
authors.lastname: Jessen
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun
keywords: axonal degeneration; demyelinating disease; neural repair; neuron-glial interaction; neuropathy