title: Neuronal Nogo-A upregulation does not contribute to ER stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina.
abstract: Nogo-A, an axonal growth inhibitory protein known to be mostly present in CNS myelin, was upregulated in retinal ganglion cells (RGCs) after optic nerve injury in adult mice. Nogo-A increased concomitantly with the endoplasmic reticulum stress (ER stress) marker C/EBP homologous protein (CHOP), but CHOP immunostaining and the apoptosis marker annexin V did not co-localize with Nogo-A in individual RGC cell bodies, suggesting that injury-induced Nogo-A upregulation is not involved in axotomy-induced cell death. Silencing Nogo-A with an adeno-associated virus serotype 2 containing a short hairpin RNA (AAV2.shRNA-Nogo-A) or Nogo-A gene ablation in knock-out (KO) animals had little effect on the lesion-induced cell stress or death. On the other hand, Nogo-A overexpression mediated by AAV2.Nogo-A exacerbated RGC cell death after injury. Strikingly, however, injury-induced sprouting of the cut axons and the expression of growth-associated molecules were markedly reduced by AAV2.shRNA-Nogo-A. The axonal growth in the optic nerve activated by the intraocular injection of the inflammatory molecule Pam3Cys tended to be lower in Nogo-A KO mice than in WT mice. Nogo-A overexpression in RGCs in vivo or in the neuronal cell line F11 in vitro promoted regeneration, demonstrating a positive, cell-autonomous role for neuronal Nogo-A in the modulation of axonal regeneration.
authors.affiliation: Brain Research Institute, University of Zürich, Switzerland. vincent.pernet@yahoo.ca
authors.forename: V
authors.initials: V
authors.lastname: Pernet
authors.forename: S
authors.initials: S
authors.lastname: Joly
authors.forename: D
authors.initials: D
authors.lastname: Dalkara
authors.forename: O
authors.initials: O
authors.lastname: Schwarz
authors.forename: F
authors.initials: F
authors.lastname: Christ
authors.forename: D
authors.initials: D
authors.lastname: Schaffer
authors.forename: J G
authors.initials: JG
authors.lastname: Flannery
authors.forename: M E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D019771:Axotomy; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D008074:Lipoproteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D000070798:Nogo Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D012160:Retina / Q000166:cytology* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017304:Annexin A5; C497250:Ddit3 protein, mouse; D008074:Lipoproteins; D009185:Myelin Proteins; D000070798:Nogo Proteins; D034741:RNA, Small Interfering; C000603201:Rtn4 protein, mouse; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D051742:Transcription Factor CHOP