Counteracting the Nogo Receptor Enhances Optic Nerve Regeneration If Retinal Ganglion Cells Are in an Active Growth State

Fischer, Dietmar; He, Zhigang; Benowitz, Larry I.

doi:10.1523/jneurosci.5119-03.2004

Cited by 255 publications

(207 citation statements)

References 42 publications

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“…Adult neuronal populations upregulate regenerationassociated genes (RAGs) after axotomy (Tetzlaff et al, 1991;Schaden et al, 1994;Bonilla et al, 2002;Tanabe et al, 2003;Fischer et al, 2004), and axonal sprouting following CNS injury, including TBI, may be accompanied by reinduction of genes ordinarily associated with developmental axonal growth (Emery et al, 2000;Abankwa et al, 2002;Emery et al, 2003;Mason et al, 2003). Over-expression of SPRRR1A can promote axonal outgrowth in vitro (Bonilla et al, 2002), and following FP brain injury, we observed an increased expression of SPRR1A(+)/NeuN (+) neurons in injured cortex and, to lesser extent, CA3 of the hippocampus although frequent SPRR1A (+)/MAP-2 (−) cells were also evident.…”

Section: Discussionmentioning

confidence: 99%

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

Marklund

Fulp

Shimizu

et al. 2006

Experimental Neurology

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Axons show a poor regenerative capacity following traumatic central nervous system (CNS) injury, partly due to the expression of inhibitors of axonal outgrowth, of which Nogo-A is considered the most important. We evaluated the acute expression of Nogo-A, the Nogo-66 receptor (NgR) and the novel small proline-rich repeat protein 1A (SPRR1A, previously undetected in brain), following experimental lateral fluid percussion (FP) brain injury in rats. Immunofluorescence with antibodies against Nogo-A, NgR and SPRR1A was combined with antibodies against the neuronal markers NeuN and microtubule-associated protein (MAP)-2 and the oligodendrocyte marker RIP, while Western blot analysis was performed for Nogo-A and NgR. Brain injury produced a significant increase in Nogo-A expression in injured cortex, ipsilateral external capsule and reticular thalamus from days 1-7 post-injury (P < 0.05) compared to controls. Increased expression of Nogo-A was observed in both RIP-and NeuN positive (+) cells in the ipsilateral cortex, in NeuN (+) cells in the CA3 region of the hippocampus and reticular thalamus and in RIP (+) cells in white matter tracts. Alterations in NgR expression were not observed following traumatic brain injury (TBI). Brain injury increased the extent of SPRR1A expression in the ipsilateral cortex and the CA3 at all post-injury time-points in NeuN (+) cells. The marked increases in Nogo-A and SPRR1A in several important brain regions suggest that although inhibitors of axonal growth may be upregulated, the injured brain is also capable of expressing proteins promoting axonal outgrowth following TBI. KeywordsNogo-A; Nogo-66 receptor; Small proline-rich repeat protein 1A (SPRR1A); Traumatic brain injury; Oligodendrocytes

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Section: Discussionmentioning

confidence: 99%

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

Marklund

Fulp

Shimizu

et al. 2006

Experimental Neurology

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“…CTB-A594-positive axons were observed on longitudinal optic nerve sections (14 mm) with a Zeiss Axioskop 2 Plus microscope (Carl Zeiss, Feldbach, Switzerland) and images were taken with a CCD video camera at x 20 magnification. The number of growing axons was estimated at different distances (50,100,150,200, 300, 400, and 500 to 1000 mm) after the lesion site. Five-six optic nerve sections were analyzed per animal.…”

Section: Moreover Inflammation-inducing Agents Such As Zymosan or Pamentioning

confidence: 99%

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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“…However, this NgR antagonist peptide does not block the inhibitory action of a second Nogo domain located in the amino terminal region of the Nogo-A isoform (Fournier et al, 2001). Viral expression of a dominant-negative version of the NgR enhances optic nerve regeneration, especially when an enhanced growth state is induced by lens injury (Fischer et al, 2004). For MAG, null mutations do not permit CST regeneration after SCI but do enhance peripheral nerve regeneration on certain genetic backgrounds (Bartsch et al, 1995;Schafer et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury

Kim

Budel

et al. 2005

Molecular and Cellular Neuroscience

102

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Axon growth after spinal injury is thought to be limited in part by myelin-derived proteins that act via the Nogo-66 Receptor (NgR). To test this hypothesis, we sought to study recovery from spinal cord injury (SCI) after inhibiting NgR transgenically with a soluble function-blocking NgR fragment. Glial fibrillary acidic protein (gfap) gene regulatory elements were used to generate mice that secrete NgR(310)ecto from astrocytes. After mid-thoracic dorsal over-hemisection injury, gfap∷ngr(310)ecto mice exhibit enhanced raphespinal and corticospinal axonal sprouting into the lumbar spinal cord. Recovery of locomotion is improved in the gfap∷ngr(310)ecto mice. These data indicate that the NgR ligands, Nogo-66, MAG, and OMgp, play a role in limiting axonal growth in the injured adult CNS and that NgR(310)ecto might provide a therapeutic means to promote recovery from SCI.

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Counteracting the Nogo Receptor Enhances Optic Nerve Regeneration If Retinal Ganglion Cells Are in an Active Growth State

Cited by 255 publications

References 42 publications

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

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

Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury

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