title: A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo.
abstract: Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal regrowth. Schwann cells are important for this regenerative process. "Sensing" damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer.
authors.affiliation: MRC Laboratory for Molecular Cell Biology and the UCL Cancer Institute, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Napoli
authors.forename: Luke A
authors.initials: LA
authors.lastname: Noon
authors.forename: Sara
authors.initials: S
authors.lastname: Ribeiro
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Kerai
authors.forename: Simona
authors.initials: S
authors.lastname: Parrinello
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rosenberg
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Collins
authors.forename: Marie C
authors.initials: MC
authors.lastname: Harrisingh
authors.forename: Ian J
authors.initials: IJ
authors.lastname: White
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.forename: Alison C
authors.initials: AC
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007962:Leukocytes / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000473:pathology / Q000503:physiopathology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001549:Benzamides; D016207:Cytokines; D004965:Estrogen Antagonists; D020800:Receptor, Nerve Growth Factor; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019938:Cyclin D1; C506614:mirdametinib; D004159:Diphenylamine; D019908:Proto-Oncogene Proteins c-raf