Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration

Fournier, Alyson E.; GrandPré, Tadzia; Strittmatter, Stephen M.

doi:10.1038/35053072

Cited by 1,018 publications

(958 citation statements)

References 13 publications

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“…In 2001, using a soluble form of Nogo-66 to screen an expression library, Strittmatter and colleagues cloned a binding partner for Nogo-66, which they termed Nogo receptor (Ngr) 32 (FIG. 2).…”

Section: Receptors For Inhibitors Of Axonal Growthmentioning

confidence: 99%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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Section: Receptors For Inhibitors Of Axonal Growthmentioning

confidence: 99%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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“…However, the topology of Nogo-A remains controversial. Although initial evidence places Nogo-66 on the extracellular surface and amino-Nogo facing intracellularly, at least some amino-Nogo can be detected on cell surfaces and both domains are inhibitory to neurite outgrowth 14,15,18,19 (FIG. 2).…”

Section: Myelin-associated Inhibitorsmentioning

confidence: 99%

Glial inhibition of CNS axon regeneration

2006

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Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of longdistance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.The nervous system has the remarkable ability to adapt and respond to various stimuli, ranging from physiological experiences associated with learning and memory, to pathological insults such as traumatic injury, stroke or neurodegenerative diseases. In addition to plasticity at the functional level, nervous system responses might also occur in the form of structural remodelling. In vivo imaging studies have shown that sensory experience can drive the formation and elimination of synapses, and that these changes might underlie the adaptive remodelling of neural circuits 1,2 . Similarly, neural injury is often accompanied by a transient period of anatomical remodel ling in the form of local sprouting at the lesion site 3 . However, although many CNS neurons can survive for years after axotomy, the severed axons ultimately fail to regenerate beyond the lesion site, in contrast to those in the PNS or embryonic nervous system. Recent evidence is beginning to reveal intriguing parallels between some of the molecular mechanisms that affect the different forms of structural plasticity, including both short-range remodelling and long-distance axon regrowth. Therefore, targeting these mechanisms might not only promote the regeneration of damaged nerve fibres, but might also enhance axon sprouting and plasticity after CNS injury. Here, we describe recent progress in under standing the inhibitory components of the adult glial environment, as well as the neuronal receptor complexes and downstream signals that mediate their effects. The limited success in targeting these pathways in vivo will then be evaluated. Finally, we discuss the physiological roles of glial inhibition in the intact nervous system, and their implications for the development of strategies to promote functional recovery after adult CNS injury. The role of extrinsic inhibitionThe regeneration failure in the adult CNS might be partly attributed to the gradual decline in the intrinsic growth ability of neurons as the animal matures. Ramón y Cajal described that, © 2006 Nature Publishing Group Correspondence to Z.H. e-mail: E-mail: zhigang.he@childrens.harvard.edu. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript after injury, the ends of lesioned axons become swollen in...

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“…[6][7][8][9][10][11] In addition to oligodendrocytes and myelin, Nogo-A is expressed in growing and immature neurons, as well as in some adult neurons. 12,13 Neurons express Nogo-A receptors such as the Nogo-66 receptor 1 (NgR1) 14 and the Nogo-A-D20-specific sphingosine 1-phosphate receptor 2 (S1PR2). 15 They can co-express them along with Nogo-A, 13 an observation that raises the possibility of cis-interactions between the ligand and its receptors within or at the cell surface of the same cell.…”

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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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Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration

Cited by 1,018 publications

References 13 publications

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

Glial inhibition of CNS axon regeneration

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

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