Neuronal Nogo-A upregulation does not contribute to ER stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina

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...

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Bibliographic Details
Published in:Cell death and differentiation 2012-07, Vol.19 (7), p.1096-1108
Main Authors: Pernet, V, Joly, S, Dalkara, D, Schwarz, O, Christ, F, Schaffer, D, Flannery, J G, Schwab, M E
Format: Article
Language:English
Subjects:
Adeno-associated virus
Animals
Annexin A5 - metabolism
Annexin V
Apoptosis
Apoptosis - drug effects
Axon sprouting
Axonogenesis
Axons
Axotomy
Biology
Brain research
CCAAT/enhancer-binding protein
Cell body
Cell death
Cells, Cultured
Central nervous system
Cytokines
Dependovirus - genetics
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Growth factors
Inflammation
Injuries
Kinases
Lipoproteins - pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin
Myelin Proteins - antagonists & inhibitors
Myelin Proteins - genetics
Myelin Proteins - metabolism
Neurites - physiology
Neurons
Neurons - metabolism
Neurosciences
Nogo protein
Nogo Proteins
Optic nerve
Original Paper
Phosphatase
Proteins
Regeneration
Regeneration - drug effects
Retina
Retina - cytology
Retina - metabolism
Retinal ganglion cells
Retinal Ganglion Cells - cytology
Retinal Ganglion Cells - metabolism
RNA
RNA Interference
RNA, Small Interfering - metabolism
Serotypes
Stress
Transcription Factor CHOP - genetics
Transcription Factor CHOP - metabolism
Tumor necrosis factor-TNF
Up-Regulation
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2011.191