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Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a p...

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Main Authors: Vajda, Flóra (Author) , Jordi, N. (Author) , Dalkara, D. (Author) , Joly, S. (Author) , Christ, F. (Author) , Tews, Björn (Author) , Schwab, M. E. (Author) , Pernet, V. (Author)
Format: Article (Journal)
Language:English
Published: 2015
In: Cell death and differentiation
Year: 2014, Volume: 22, Issue: 2, Pages: 323-335
ISSN:1476-5403
DOI:10.1038/cdd.2014.147
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/cdd.2014.147
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/cdd2014147
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Author Notes:F. Vajda, N. Jordi, D. Dalkara, S. Joly, F. Christ, B. Tews, M.E. Schwab and V. Pernet

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520 |a Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre+/−xRtn4/Nogo-Aflox/flox) and neuron-specific (Thy1-Cretg+xRtn4flox/flox) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS. 
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