title: Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve.
abstract: 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-A(flox/flox)) and neuron-specific (Thy1-Cre(tg+)xRtn4(flox/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 Rtn4(flox/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.
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Vajda
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Jordi
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris F-75012, France.
authors.forename: D
authors.initials: D
authors.lastname: Dalkara
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Joly
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Christ
authors.affiliation: 1] Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland [2] German Cancer Research Center (DKFZ), Heidelberg University, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Tews
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: M E
authors.initials: ME
authors.lastname: Schwab
authors.affiliation: Brain Research Institute, University of Zurich, and Department of Health Sciences and Technology, ETH Zurich, CH-8057 Zurich, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Pernet
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics*; D009186:Myelin Sheath / Q000502:physiology; D009409:Nerve Crush; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology; D000070798:Nogo Proteins; D020221:Optic Nerve Injuries / Q000628:therapy*; D012038:Regeneration; D012165:Retinal Ganglion Cells / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse