title: NF-κB controls axonal regeneration and degeneration through cell-specific balance of RelA and p50 in the adult CNS.
abstract: NF-κB is dually involved in neurogenesis and brain pathology. Here, we addressed its role in adult axoneogenesis by generating mutations of RelA (p65) and p50 (also known as NFKB1) heterodimers of canonical NF-κB. In addition to RelA activation in astrocytes, optic nerve axonotmesis caused a hitherto unrecognized induction of RelA in growth-inhibitory oligodendrocytes. Intraretinally, RelA was induced in severed retinal ganglion cells and was also expressed in bystander Müller glia. Cell-type-specific deletion of transactivating RelA in neurons and/or macroglia stimulated axonal regeneration in a distinct and synergistic pattern. By contrast, deletion of the p50 suppressor subunit promoted spontaneous and post-injury Wallerian degeneration. Growth effects mediated by RelA deletion paralleled a downregulation of growth-inhibitory Cdh1 (officially known as FZR1) and upregulation of the endogenous Cdh1 suppressor EMI1 (officially known as FBXO5). Pro-degenerative loss of p50, however, stabilized retinal Cdh1. In vitro, RelA deletion elicited opposing pro-regenerative shifts in active nuclear and inactive cytoplasmic moieties of Cdh1 and Id2. The involvement of NF-κB and cell-cycle regulators such as Cdh1 in regenerative processes of non-replicative neurons suggests novel mechanisms by which molecular reprogramming might be executed to stimulate adult axoneogenesis and treat central nervous system (CNS) axonopathies.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany rhaenold@fli-leibniz.de.
authors.forename: Ronny
authors.initials: R
authors.lastname: Haenold
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.affiliation: Friedrich Schiller University of Jena Medical School, Institute of Diagnostic and Interventional Radiology, Medical Physics Group, Philosophenweg 3, 07743 Jena, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Herrmann
authors.affiliation: Friedrich Schiller University of Jena, Institute of General Zoology and Animal Physiology, Erbertstrasse 1, 07743 Jena, Germany rhaenold@fli-leibniz.de.
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Schmidt
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Krempler
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Engelmann
authors.affiliation: Max Planck Institute for Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Friedrich Schiller University of Jena Medical School, Institute of Diagnostic and Interventional Radiology, Medical Physics Group, Philosophenweg 3, 07743 Jena, Germany.
authors.forename: Jürgen R
authors.initials: JR
authors.lastname: Reichenbach
authors.forename: Siegrid
authors.initials: S
authors.lastname: Löwel
authors.affiliation: Friedrich Schiller University of Jena, Institute of General Zoology and Animal Physiology, Erbertstrasse 1, 07743 Jena, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Löwel
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kretz
mesh_terms: D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D064200:Cdh1 Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000378:metabolism / Q000473:pathology
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D052002:NF-kappa B p50 Subunit; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C073701:Nfkb1 protein, mouse
keywords: Anaphase-promoting complex; Axonal regeneration; Cdh1; Manganese-enhanced MRI; NF-κB; RelA; Wallerian degeneration; p50; p65