title: Neuronal c-Jun is required for successful axonal regeneration, but the effects of phosphorylation of its N-terminus are moderate.
abstract: Although neural c-Jun is essential for successful peripheral nerve regeneration, the cellular basis of this effect and the impact of c-Jun activation are incompletely understood. In the current study, we explored the effects of neuron-selective c-Jun deletion, substitution of serine 63 and 73 phosphoacceptor sites with non-phosphorylatable alanine, and deletion of Jun N-terminal kinases 1, 2 and 3 in mouse facial nerve regeneration. Removal of the floxed c-jun gene in facial motoneurons using cre recombinase under control of a neuron-specific synapsin promoter (junΔS) abolished basal and injury-induced neuronal c-Jun immunoreactivity, as well as most of the molecular responses following facial axotomy. Absence of neuronal Jun reduced the speed of axonal regeneration following crush, and prevented most cut axons from reconnecting to their target, significantly reducing functional recovery. Despite blocking cell death, this was associated with a large number of shrunken neurons. Finally, junΔS mutants also had diminished astrocyte and microglial activation and T-cell influx, suggesting that these non-neuronal responses depend on the release of Jun-dependent signals from neighboring injured motoneurons. The effects of substituting serine 63 and 73 phosphoacceptor sites (junAA), or of global deletion of individual kinases responsible for N-terminal c-Jun phosphorylation were mild. junAA mutants showed decrease in neuronal cell size, a moderate reduction in post-axotomy CD44 levels and slightly increased astrogliosis. Deletion of Jun N-terminal kinase (JNK)1 or JNK3 showed delayed functional recovery; deletion of JNK3 also interfered with T-cell influx, and reduced CD44 levels. Deletion of JNK2 had no effect. Thus, neuronal c-Jun is needed in regeneration, but JNK phosphorylation of the N-terminus mostly appears to not be required for its function.
authors.affiliation: Perinatal Brain Repair Group, Inst Women's Health, University College London, London, UK.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Ruff
authors.forename: Nils
authors.initials: N
authors.lastname: Staak
authors.forename: Smriti
authors.initials: S
authors.lastname: Patodia
authors.forename: Mark
authors.initials: M
authors.lastname: Kaswich
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.forename: Clive
authors.initials: C
authors.lastname: Da Costa
authors.forename: Stephan
authors.initials: S
authors.lastname: Brecht
authors.forename: Milan
authors.initials: M
authors.lastname: Makwana
authors.forename: Xavier
authors.initials: X
authors.lastname: Fontana
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.forename: Prakasham
authors.initials: P
authors.lastname: Rumajogee
authors.forename: Matthias
authors.initials: M
authors.lastname: Galiano
authors.forename: Marion
authors.initials: M
authors.lastname: Bohatschek
authors.forename: Thomas
authors.initials: T
authors.lastname: Herdegen
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
mesh_terms: D000818:Animals; D001284:Atrophy; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D016923:Cell Death; D005260:Female; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000502:physiology; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D010766:Phosphorylation; D017354:Point Mutation / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*
chemical_list: D018960:Hyaluronan Receptors; D016755:Proto-Oncogene Proteins c-jun; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8