Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions

Thallmair, Michaela; Metz, Gerlinde A. S.; Z'Graggen, Werner Josef; Raineteau, Olivier; Kartje, Gwendolyn L.; Schwab, Martin E.

doi:10.1038/373

Cited by 359 publications

(270 citation statements)

References 46 publications

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“…2 Neutralizing Nogo-A by functionblocking antibodies or genetic knockout (KO) has been shown to improve axonal sprouting and regeneration in the injured spinal cord and brain. [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).…”

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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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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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“…163 Exogenous NT-3 promotes sprouting of intact CST axons developmentally 197 and following rubrospinal tract ablation in adults. 184 Like neurotrophic factors, neutralizing inhibitory myelin and ECM molecules can promote sprouting of some intact systems: blocking Nogo-A promotes sprouting of adult CST axons, 198 and digestion of glial scarassociated CSPGs promotes behavioral recovery following dorsal column injury in the absence of robust regeneration of injured axons. 92 Bridging the site of SCI Neuroprotective treatments might soon increase the continuity across the lesion site (see 'Neuroprotection in the setting of SCI' above), but this advancement may not eliminate the need for bridging transplants.…”

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 99%

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

2005

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Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast of villains but also a company of therapeutic targets, many of which have yet to be fully exploited. We next discuss recent progress in the fields of bridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects of SCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role.Spinal Cord (2005) 43, 134-161.

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“…79 The result has been that in several CNS injury paradigms including spinal cord injuries, infusion of this antibody has produced regeneration of some axons. 80 In addition, it appears as though it can induce the collateral sprouting of spared corticospinal tract axons following unilateral pyramidal tract lesions 81,82 (see also Vertical Target 4). Of course, IN-1 is only one of a large number of possible inhibitory molecules.…”

Section: Inhibition Within the Cnsmentioning

confidence: 99%

“…81,82 In this study, the anatomical and functional e ects of the IN-1 antibody were examined following a well de®ned lesion to the CST. The corticospinal projections of the non-lesioned CST and the corticorubral and corticopontine projections of the lesioned CST were examined and in both cases extensive branching was observed in lesioned rats treated with IN-1.…”

Section: Axonal Branchingmentioning

confidence: 99%

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Progress in Spinal Cord Research - A refined strategy for the International Spinal Research Trust

2000

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Achieving regeneration in the central nervous system represents one of the greatest intellectual and practical challenges in neurobiology, and yet it is an absolute requirement if spinal cord injury patients are to have any hope of recovery. The mission of the International Spinal Research Trust (ISRT), established in 1980, is to raise money speci®cally for spinal research, with a view to ending the permanence of paralysis caused by spinal cord injury. This review summarises some of the major steps forward made in recent years in understanding the mechanisms involved in spinal cord injury and where these discoveries ®t in with the ISRT's overall objectives. We review approaches aimed at (1) preventing immediate adverse reactions to injury such as neuronal death and scar formation; (2) minimising inhibitory properties of the CNS environment and maximising the growth potential of damaged neurons; (3) understanding axonal guidance systems that will be required for directed outgrowth and functional reconnection; and (4) optimising the function of surviving systems. We also discuss infrastructural' prerequisites for applying knowledge gained through spinal research to the clinical condition, including basic scienti®c issues such as developing representative animal models of spinal cord injury and sensitive quantitative methods for assessing growth and functional restoration. In addition, we point out the importance of communication. The need to share knowledge between research groups is vital for advancing our understanding of injury and repair mechanisms. Equally important is the need for communication between basic scientists and clinicians which will be essential for what is the ultimate goal of the ISRT, the development of relevant treatment strategies that will prove bene®cial to the spinal injured patient. Spinal Cord (2000) 38, 449 ± 472

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Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions

Cited by 359 publications

References 46 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

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

Progress in Spinal Cord Research - A refined strategy for the International Spinal Research Trust

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