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

Pernet, Vincent; Joly, Sandrine; Dalkara, Deniz; Schwarz, Olivia; Christ, Frauke; Schaffer, David V.; Flannery, John G.; Schwab, Martin E.

doi:10.1038/cdd.2011.191

Cited by 45 publications

(68 citation statements)

References 41 publications

(61 reference statements)

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“…The injury-induced growth response of RGCs was further analyzed by following the gene expression changes of Sprr1A and growth-associated protein 43 (Gap-43), two known indicators of neuronal growth in the CNS and the peripheral nervous system. 29,[32][33][34] The mRNA levels of the two growth markers were increased 5 days after optic nerve crush and were more elevated in the Cnp-Cre þ / À xRtn4 flox/flox KO retinae than in control samples ( Supplementary Figures S2A and B). These data show that the targeted deletion of Nogo-A in myelinating cells of the optic nerve enhances the neuronal growth response after axonal injury, in marked contrast with our previous analysis in conventional, systemic Nogo-A KO animals.…”

Section: Resultsmentioning

confidence: 99%

“…These data show that the targeted deletion of Nogo-A in myelinating cells of the optic nerve enhances the neuronal growth response after axonal injury, in marked contrast with our previous analysis in conventional, systemic Nogo-A KO animals. 29 Nogo-A deletion in Cnp-Cre þ / À xRtn4 flox/flox mice enhances inflammation-induced axonal regeneration after optic nerve injury. The growth state of RGCs can be enhanced by intraocular injection of inflammatory agents such as the Toll-like receptor 2 agonist Zymosan.…”

Section: Resultsmentioning

confidence: 99%

“…Western blot analysis revealed a downregulation of Nogo-A by B85% in glial Nogo-A KO retinae (Figure 3a), although no oligodendrocytes are present in this tissue. As in the intact retina of adult mice the bulk of Nogo-A is expressed by Mü ller glial cells, 29 To genetically ablate Nogo-A in RGCs, a neuron-specific Nogo-A KO mouse line was generated by crossing mice expressing Cre-recombinase under the control of the Thy1 promoter 42 with Rtn4 flox/flox mice ( Figure 5a). By western blotting in the optic nerve, neuronal KOs showed a Nogo-A reduction by B40% compared with B80% downregulation in glial KOs (Figure 5b).…”

Section: Compensatory Upregulation Of Ephrina3 and Epha4mentioning

confidence: 99%

“…27,28 In injured adult retinal ganglion cells (RGCs), silencing neuronal Nogo-A resulted in a marked reduction of regenerative sprouting and decreased expression of growth-associated molecules. 29 Furthermore, in the optic nerve, axonal regeneration was not improved in conventional Nogo-A KO animals, in which both glial and neuronal Nogo-A were deleted. 29 The present study therefore aimed to investigate whether glial and neuronal Nogo-A differently influence axonal growth in vivo using cell typespecific Nogo-A KO mouse lines and adeno-associated virus (AAV)-mediated recombination of the Nogo-A gene in neurons.…”

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confidence: 98%

“…29 Furthermore, in the optic nerve, axonal regeneration was not improved in conventional Nogo-A KO animals, in which both glial and neuronal Nogo-A were deleted. 29 The present study therefore aimed to investigate whether glial and neuronal Nogo-A differently influence axonal growth in vivo using cell typespecific Nogo-A KO mouse lines and adeno-associated virus (AAV)-mediated recombination of the Nogo-A gene in neurons. The results show that significantly more axons grew through the lesion site in the oligodendrocyte-specific Nogo-A KO mice.…”

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

et al. 2014

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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 þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Compensatory Upregulation Of Ephrina3 and Epha4mentioning

confidence: 99%

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confidence: 98%

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

et al. 2014

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Neuronal Nogo‐A in New‐born Retinal Ganglion Cells: Implication for the Formation of the Age‐related Fiber Order in the Optic Tract

Liu

Chan

et al. 2016

The Anatomical Record

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Nogo-A is highly expressed in oligodendrocytes in the adult central nervous system (CNS). Recently it was found that Nogo-A is also expressed in some neuronal types during development. Here, we examined the expression pattern of Nogo-A in both the retina and optic tract (OT) of mouse embryos from E12 to E15. After perturbation of its function in the OT for 5 hr in the brain slice culture system using a Nogo-A specific antibody or antagonist of its receptor (NEP1-40), the optic nerve fibers and growth cones were traced with DiI. We showed that most Tuj-1 positive new-born neurons at E12 were Nogo-A positive. At E15, retinal neurons reduced the Nogo-A expression. It was worth noting that some projecting axons expressed Nogo-A along the retinofugal pathway. On the basis of their specific locations within the superficial half of the OT and the colocalization with GAP-43 (a marker for the newly born growth cones and axons), we concluded that those Nogo-A positive axons were the newly arrived retinal fibers. Blocking the function of Nogo-A with Nogo-A antibody or NEP1-40 resulted in the shift of DiI labeled axons and growth cones from the superficial half to the whole depth of the OT. These results indicate that Nogo-A in the newly born retinal ganglion cells (RGCs) and their axons are involved in sorting out the newly arrived axons to the subpial region of the OT. Anat Rec, 299:1027Rec, 299: -1036Rec, 299: , 2016. V C 2016 Wiley Periodicals, Inc.Key words: Nogo-A; RGCs; axon guidance; optic tract; mouse embryoAxon outgrowth and pathfinding are important aspects of neural development. The RGCs, which are the only neuronal type which send axons out of the eye to connect with targets in the brain, provide a good model to study axon guidance and pathfinding. During the development of the visual pathway, various retinofugal projections are topographically arranged within the superior colliculus and the lateral geniculate nucleus (Udin and Fawcett, 1988). Thus, the

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Nogo‐A does not inhibit retinal axon regeneration in the lizard Gallotia galloti

Lang

Romero-Aleman

Dobson

et al. 2016

J of Comparative Neurology

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The myelin-associated protein Nogo-A contributes to the failure of axon regeneration in the mammalian central nervous system (CNS). Inhibition of axon growth by Nogo-A is mediated by the Nogo-66 receptor (NgR). Nonmammalian vertebrates, however, are capable of spontaneous CNS axon regeneration, and we have shown that retinal ganglion cell (RGC) axons regenerate in the lizard Gallotia galloti. Using immunohistochemistry, we observed spatiotemporal regulation of Nogo-A and NgR in cell bodies and axons of RGCs during ontogeny. In the adult lizard, expression of Nogo-A was associated with myelinated axon tracts and upregulated in oligodendrocytes during RGC axon regeneration. NgR became upregulated in RGCs following optic nerve injury. In in vitro studies, Nogo-A-Fc failed to inhibit growth of lizard RGC axons. The inhibitor of protein kinase A (pkA) activity KT5720 blocked growth of lizard RGC axons on substrates of Nogo-A-Fc, but not laminin. On patterned substrates of Nogo-A-Fc, KT5720 caused restriction of axon growth to areas devoid of Nogo-A-Fc. Levels of cyclic adenosine monophosphate (cAMP) were elevated over sustained periods in lizard RGCs following optic nerve lesion. We conclude that Nogo-A and NgR are expressed in a mammalian-like pattern and are upregulated following optic nerve injury, but the presence of Nogo-A does not inhibit RGC axon regeneration in the lizard visual pathway. The results of outgrowth assays suggest that outgrowth-promoting substrates and activation of the cAMP/pkA signaling pathway play a key role in spontaneous lizard retinal axon regeneration in the presence of Nogo-A. Restriction of axon growth by patterned Nogo-A-Fc substrates suggests that Nogo-A may contribute to axon guidance in the lizard visual system. J. Comp. Neurol. 525:936-954, 2017. © 2016 Wiley Periodicals, Inc.

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

Cited by 45 publications

References 41 publications

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

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

Neuronal Nogo‐A in New‐born Retinal Ganglion Cells: Implication for the Formation of the Age‐related Fiber Order in the Optic Tract

Nogo‐A does not inhibit retinal axon regeneration in the lizard Gallotia galloti

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