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

Li, Shuxin; Kim, Jieun; Budel, Stephane; Hampton, Thomas G.; Strittmatter, Stephen M.

doi:10.1016/j.mcn.2004.12.008

Cited by 100 publications

(76 citation statements)

References 55 publications

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“…Interfering with the Nogo-NgR axis by antagonizing the inhibitory effects of NogoA pharmacologically using the monoclonal antibody IN-1 [25][26][27][28][29] or in nogo-a knockout mice [30][31][32] has shown significant long-distance growth of damaged CST axons after dorsal hemisection with concomitant restoration of locomotor function. Similar results were observed with therapies that antagonized the activation of NgR1, using either the Nogo receptor antagonist peptide NEP1-40 or a soluble version of NgR1 called NgR(310)ecto-Fc [33][34][35][36][37]. These studies directly correlate the growth of damaged CST axons into the caudal spinal cord with recovery of locomotion.…”

Section: Myelin-associated Inhibitors and Axonal Growthsupporting

confidence: 67%

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cafferty

McGee

Strittmatter

2008

Trends in Neurosciences

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141

108

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Loss of function after neurological injury frequently occurs through the interruption of axonal connectivity, rather than through cell loss. Functional deficits persist because a multitude of inhibitory factors in degenerating myelin and astroglial scar prevent axonal growth in the adult brain and spinal cord. Given the high clinical significance of achieving functional recovery through axonal growth, substantial research effort has been, and will be, devoted toward this desirable goal. Unfortunately, the labels commonly used in the literature to categorize post-injury axonal anatomy might hinder advancement. In this article, we present an argument for the importance of developing precise terms that describe axonal growth in terms of the inciting event, the distance of axonal extension and the timing of axonal growth. The phenotypes produced by molecular interventions that overcome astroglial scar or myelin-associated inhibitors are reframed and discussed in this context.

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Section: Myelin-associated Inhibitors and Axonal Growthsupporting

confidence: 67%

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cafferty

McGee

Strittmatter

2008

Trends in Neurosciences

Self Cite

141

108

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“…Similar results were obtained by transgenic expression of the same NgR1 ectodomain in mice (Li et al, 2005). The pattern of axonal sprouting in these two studies appears to differ from that of the study with intrathecal administration of NEP1-40 in rats where ectopic CST fibers in the white matter above and below injury are the hallmark.…”

Section: Ngr1supporting

confidence: 55%

“…Intrathecal delivery of an NgR1 ectodomain that acts as an NgR1 antagonist by competing with endogenous NgR1 in binding the inhibitory ligands (Nogo, MAG and OMgp) leads to enhanced CST and serotonergic fiber regeneration and sprouting, and improved functional recovery in rats Li et al, 2005). Similar results were obtained by transgenic expression of the same NgR1 ectodomain in mice (Li et al, 2005).…”

Section: Ngr1mentioning

confidence: 55%

White matter inhibitors in CNS axon regeneration failure

Xie

Zheng

2008

Experimental Neurology

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Multiple lines of evidence have indicated that the inability of adult mammalian central nervous system (CNS) axons to regenerate after injury is partly due to the growth inhibitory property of central myelin. Three prototypical myelin-associated inhibitors of neurite outgrowth have been identified, including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp). These inhibitory ligands, their receptors and signaling pathways are being intensively investigated for their roles in CNS axon regeneration failure. In addition, several members of the axon guidance molecules have been implicated in restricting CNS axon regeneration, some of which are expressed by mature oligodendrocytes. Here we review in vitro and in vivo studies of these molecules in neurite growth and in axon regeneration failure and discuss the implications of these studies. While the increasing number of potential axon regeneration inhibitors highlights the complexity of the restrictive CNS environment, it provides new windows of opportunity as well as new challenges for therapeutic development for spinal cord injury and related neurological conditions.

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“…MAG, nogo, and oligodendrocyte myelin glycoprotein signal through a receptor complex consisting of the nogo receptor, p75, and LINGO (Bandtlow and Dechant, 2004). Genetic deletion of the nogo receptor does not foster regeneration, but the transgenic expression of a soluble receptor antagonist does (Li et al, 2005;Zheng et al, 2005). Why genetic targeting of known growthinhibitory molecules often fails but pharmacological targeting succeeds is unknown.…”

Section: Discussionmentioning

confidence: 99%

Antibodies against the NG2 Proteoglycan Promote the Regeneration of Sensory Axons within the Dorsal Columns of the Spinal Cord

Tan¹,

Colletti²,

Rorai³

et al. 2006

J. Neurosci.

124

138

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The NG2 chondroitin sulfate proteoglycan inhibits axon growth in vitro. Levels of NG2 increase rapidly in the glial scars that form at sites of CNS injury, suggesting that NG2 may inhibit axon regeneration. To determine the functions of NG2, we infused mixtures of neutralizing or non-neutralizing anti-NG2 monoclonal antibodies into the dorsally transected adult rat spinal cord and analyzed the regeneration of ascending mechanosensory axons anatomically. At 1 week after injury, ascending sensory axons in control animals terminated caudal to the lesion within an area containing dense deposits of NG2 immunoreactivity. In animals treated with the neutralizing anti-NG2 antibodies, labeled axons penetrated the caudal border of the lesion and grew into and beyond the lesion center. The low intrinsic growth capacity of adult neurons may also limit the ability of damaged axons to regenerate. To enhance growth, we combined antibody treatment with a peripheral nerve conditioning lesion. After a conditioning lesion and treatment with control, non-neutralizing antibodies, many sensory axons grew into the lesion core. These axons did not grow past the rostral border of the lesion; rather, they grew along the dorsal surface of the spinal cord and within any remaining pieces of the dorsal roots. In contrast, combining a peripheral nerve conditioning lesion with neutralizing anti-NG2 antibodies resulted in sensory axon regeneration past the glial scar and into the white matter rostral to the injury site. The combinatorial approach used here that neutralizes extrinsic inhibition and increases intrinsic growth results in anatomically correct axon regeneration, a prerequisite for functional recovery.

show abstract

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

Cited by 100 publications

References 55 publications

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Axonal growth therapeutics: regeneration or sprouting or plasticity?

White matter inhibitors in CNS axon regeneration failure

Antibodies against the NG2 Proteoglycan Promote the Regeneration of Sensory Axons within the Dorsal Columns of the Spinal Cord

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