title: Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.
abstract: Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin. The molecular control, functional role and origin of these central remyelinating Schwann cells is currently unknown. The growth factor neuregulin-1 (Nrg1, encoded by NRG1) is a key signalling factor controlling myelination in the peripheral nervous system, via signalling through ErbB tyrosine kinase receptors. Here we examined whether Nrg1 is required for Schwann cell-mediated remyelination of central dorsal column axons and whether Nrg1 ablation influences the degree of spontaneous remyelination and functional recovery following spinal cord injury. In contused adult mice with conditional ablation of Nrg1, we found an absence of Schwann cells within the spinal cord and profound demyelination of dorsal column axons. There was no compensatory increase in oligodendrocyte remyelination. Removal of peripheral input to the spinal cord and proliferation studies demonstrated that the majority of remyelinating Schwann cells originated within the injured spinal cord. We also examined the role of specific Nrg1 isoforms, using mutant mice in which only the immunoglobulin-containing isoforms of Nrg1 (types I and II) were conditionally ablated, leaving the type III Nrg1 intact. We found that the immunoglobulin Nrg1 isoforms were dispensable for Schwann cell-mediated remyelination of central axons after spinal cord injury. When functional effects were examined, both global Nrg1 and immunoglobulin-specific Nrg1 mutants demonstrated reduced spontaneous locomotor recovery compared to injured controls, although global Nrg1 mutants were more impaired in tests requiring co-ordination, balance and proprioception. Furthermore, electrophysiological assessments revealed severely impaired axonal conduction in the dorsal columns of global Nrg1 mutants (where Schwann cell-mediated remyelination is prevented), but not immunoglobulin-specific mutants (where Schwann cell-mediated remyelination remains intact), providing robust evidence that the profound demyelinating phenotype observed in the dorsal columns of Nrg1 mutant mice is related to conduction failure. Our data provide novel mechanistic insight into endogenous regenerative processes after spinal cord injury, demonstrating that Nrg1 signalling regulates central axon remyelination and functional repair and drives the trans-differentiation of central precursor cells into peripheral nervous system-like Schwann cells that remyelinate spinal axons after injury. Manipulation of the Nrg1 system could therefore be exploited to enhance spontaneous repair after spinal cord injury and other central nervous system disorders with a demyelinating pathology.media-1vid110.1093/brain/aww039_video_abstractaww039_video_abstract.
authors.affiliation: The Wolfson Centre for Age-Related Diseases, Regeneration Group, King's College London, Guy's Campus, London Bridge, London, UK.
authors.forename: Katalin
authors.initials: K
authors.lastname: Bartus
authors.affiliation: Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.affiliation: The Wolfson Centre for Age-Related Diseases, Regeneration Group, King's College London, Guy's Campus, London Bridge, London, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Hernandez-Miranda
authors.affiliation: Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Dawes
authors.affiliation: Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford, UK.
authors.forename: Florence R
authors.initials: FR
authors.lastname: Fricker
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany Charité Universitätsmedizin Berlin, Charitéplatz, Berlin, Germany.
authors.forename: Alistair N
authors.initials: AN
authors.lastname: Garratt
authors.affiliation: The Wolfson Centre for Age-Related Diseases, Regeneration Group, King's College London, Guy's Campus, London Bridge, London, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, Canada.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Ramer
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.affiliation: Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford, UK elizabeth.bradbury@kcl.ac.uk david.bennett@ndcn.ox.ac.uk.
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
authors.affiliation: The Wolfson Centre for Age-Related Diseases, Regeneration Group, King's College London, Guy's Campus, London Bridge, London, UK elizabeth.bradbury@kcl.ac.uk david.bennett@ndcn.ox.ac.uk.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bradbury
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D049109:Cell Proliferation; D003711:Demyelinating Diseases / Q000503:physiopathology; D005260:Female; D051379:Mice; D008817:Mice, Mutant Strains; D009048:Motor Skills / Q000502:physiology; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009431:Neural Conduction / Q000502:physiology; D020890:Neuregulin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D020127:Recovery of Function / Q000235:genetics / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000235:genetics / Q000503:physiopathology*; D058630:Spinal Cord Regeneration / Q000502:physiology*
chemical_list: D020890:Neuregulin-1; D020033:Protein Isoforms
keywords: axon degeneration; demyelination; remyelination; spinal cord injury; transgenic model