The Nogo-66 Receptor NgR1 Is Required Only for the Acute Growth Cone-Collapsing But Not the Chronic Growth-Inhibitory Actions of Myelin Inhibitors

Chivatakarn, Onanong; Kaneko, Shinjiro; He, Zhigang; Tessier‐Lavigne, Marc; Giger, Roman J.

doi:10.1523/jneurosci.1541-07.2007

Cited by 95 publications

(100 citation statements)

References 41 publications

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“…It has widely been assumed that the chronic axon growth inhibitory effect of CNS inhibitors is reflected in the acute collapse response. However, a previous study (38) has clearly demonstrated that the acute growth cone collapse and the chronic axon growth inhibition are mechanistically distinct events, suggesting that MT-and actin-based growth cone responses and subsequent axon growth can be distinguished.…”

Section: Discussionmentioning

confidence: 96%

Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules

Hur¹,

Yang²,

Kim³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

134

155

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Neurons in the central nervous system (CNS) fail to regenerate axons after injuries due to the diminished intrinsic axon growth capacity of mature neurons and the hostile extrinsic environment composed of a milieu of inhibitory factors. Recent studies revealed that targeting a particular group of extracellular inhibitory factors is insufficient to trigger long-distance axon regeneration. Instead of antagonizing the growing list of impediments, tackling a common target that mediates axon growth inhibition offers an alternative strategy to promote axon regeneration. Neuronal growth cone, the machinery that derives axon extension, is the final converging target of most, if not all, growth impediments in the CNS. In this study, we aim to promote axon growth by directly targeting the growth cone. Here we report that pharmacological inhibition or genetic silencing of nonmuscle myosin II (NMII) markedly accelerates axon growth over permissive and nonpermissive substrates, including major CNS inhibitors such as chondroitin sulfate proteoglycans and myelin-associated inhibitors. We find that NMII inhibition leads to the reorganization of both actin and microtubules (MTs) in the growth cone, resulting in MT reorganization that allows rapid axon extension over inhibitory substrates. In addition to enhancing axon extension, we show that local blockade of NMII activity in axons is sufficient to trigger axons to grow across the permissive-inhibitory border. Together, our study proposes NMII and growth cone cytoskeletal components as effective targets for promoting axon regeneration.myelin | glial scar | multi-compartment neuronal culture chamber

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Section: Discussionmentioning

confidence: 96%

Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules

Hur¹,

Yang²,

Kim³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

134

155

View full text Add to dashboard Cite

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“…(See ref. 18 for a discussion of these studies.) Several groups have reported significant improvements in spinal cord function through blockage of this inhibition, but determining the degree to which normal spinal circuitry is reestablished has proven difficult.…”

Section: Discussionmentioning

confidence: 99%

“…This finding might be explained by a dynamic inhibitory influence of myelin. Intact myelin and myelin debris produced by damaged axons have different inhibitory properties (18). Inhibition mediated by myelin produced by oligodendrocytes increases during the first week after DR crush injury as myelin degenerates (5).…”

Section: Discussionmentioning

confidence: 99%

Topographically specific regeneration of sensory axons in the spinal cord

Harvey

Gong

Rossomando

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.artemin | central nervous system regeneration | dorsal root | soluble Nogo receptor peptide | specificity G rowth of damaged axons in the adult spinal cord is inhibited by the presence of myelin-associated proteins, up-regulation of proteoglycan expression, and the absence of appropriate growth factors. Several agents that can partially overcome this inhibition permit some regeneration of spinal axons in contusion or transaction models of spinal cord injury (SCI) (1-4); however, the limited regeneration and difficulty in labeling specific subclasses of axons with known projection patterns within the spinal cord have impeded progress in determining whether these regenerated projections are specific.The regeneration of sensory axons into the spinal cord after dorsal root (DR) crush provides a useful preparation for assessing the precision with which regenerating axons project back to appropriate target areas within the central nervous system (CNS). Regrowth of damaged sensory axons within the spinal cord can be visualized by injecting neurotracers into peripheral nerves. Identification of individual classes of axons can be achieved by making injections close to target tissues where nerve branches contain single classes of sensory afferents. Because only the DRs are damaged, the architecture of the spinal cord is left intact, allowing clear identification of the central projections of regenerated axons.Without treatment, sensory axons regenerate only to the DR entry zone (DREZ), where they encounter inhibitory barriers within the CNS (5, 6). Application of two agents-a soluble Nogo receptor peptide (sNgR), which binds to Nogo receptor ligands and abrogates their inhibitory effect (7), and artemin (ART), a member of the glial-derived neurotrophic factor familypromote robust regeneration of sensory axons after DR crush (8, 9). The specificity of projections of specific classes of...

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“…We chose to assess growth cone collapse in DRGs, widely accepted as an NgR1-dependent response to myelin (26,27). We treated FLAG-NgR1-transfected COS-7 cells with recombinant MMPs and identified 0.75 M recombinant MT1-MMP and 1.5 M recombinant MT3-MMP as appropriate doses to remove NgR1 from the cell surface (Fig.…”

Section: Mt1-mmp and Mt3-mmp Attenuate Myelin-dependent Growth Conementioning

confidence: 99%

Membrane-type Matrix Metalloproteinase-3 Regulates Neuronal Responsiveness to Myelin through Nogo-66 Receptor 1 Cleavage

Ferraro

Morrison

Overall

et al. 2011

Journal of Biological Chemistry

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Nogo-66 receptor 1 (NgR1) is a glycosylphosphatidylinositolanchored receptor for myelin-associated inhibitors that restricts plasticity and axonal regrowth in the CNS. NgR1 is cleaved from the cell surface of SH-SY5Y neuroblastoma cells in a metalloproteinase-dependent manner; however, the mechanism and physiological consequence of NgR1 shedding have not been explored. We now demonstrate that NgR1 is shed from multiple populations of primary neurons. Through a loss-offunction approach, we found that membrane-type matrix metalloproteinase-3 (MT3-MMP) regulates endogenous NgR1 shedding in primary neurons. Neuronal knockdown of MT3-MMP resulted in the accumulation of NgR1 at the cell surface and reduced the accumulation of the NgR1 cleavage fragment in medium conditioned by cortical neurons. Recombinant MT1-, MT2-, MT3-, and MT5-MMPs promoted NgR1 shedding from the surface of primary neurons, and this treatment rendered neurons resistant to myelin-associated inhibitors. Introduction of a cleavage-resistant form of NgR1 reconstitutes the neuronal response to these inhibitors, demonstrating that specific metalloproteinases attenuate neuronal responses to myelin in an NgR1-dependent manner.Nogo-66 receptor 1 (NgR1) 2 was originally identified as a receptor for myelin-associated inhibitors (MAIs) (1). NgR1 is a glycosylphosphatidylinositol (GPI)-anchored protein that complexes with LINGO and p75 NTR or TAJ/TROY to mediate neurite outgrowth inhibition of neurons (2). Neutralization of NgR1 attenuates the inhibitory effects of MAIs in vitro and promotes regeneration following CNS trauma in vivo (3). Further studies have suggested that NgR1 plays a protective role in Alzheimer disease (4), that NgR1 variants contribute to increased risk of schizophrenia (5), and that NgR1 limits plasticity in the hippocampus (6) and in the visual cortex (7). Understanding the mechanisms that regulate NgR1 will have important implications for CNS plasticity, disease, and regeneration.NgR1 shed from the cell surface is a soluble fragment spanning amino acids 1-358 (8). This fragment is similar to NgREcto (amino acids 1-310), a dominant-negative protein that promotes axonal regeneration in vitro and in vivo by antagonizing MAI signaling (9, 10). The shed NgR1 product can be detected in human cerebral spinal fluid, indicative of a physiological role for this fragment.NgR1 shedding is blocked by the metalloproteinase inhibitor PKF226 -967. Metalloproteinases are a family of zinc-dependent proteases that include ADAM (a disintegrin and metalloproteinases) and secreted or membrane-type matrix metalloproteinases (MT-MMPs) (11). MT1-MMP (MMP-14), MT2-MMP (MMP-15), MT3-MMP (MMP-16), and MT5-MMP (MMP-24) anchor to the cell surface with a transmembrane domain, whereas MT4-MMP (MMP-17) and MT6-MMP (MMP-25) attach with a GPI anchor. MMPs have been widely studied for their capacity to degrade the extracellular matrix and to promote invasion and migration of tumor cells; however, it is also known that they can cleave a wide range of ligands and receptors...

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The Nogo-66 Receptor NgR1 Is Required Only for the Acute Growth Cone-Collapsing But Not the Chronic Growth-Inhibitory Actions of Myelin Inhibitors

Cited by 95 publications

References 41 publications

Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules

Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules

Topographically specific regeneration of sensory axons in the spinal cord

Membrane-type Matrix Metalloproteinase-3 Regulates Neuronal Responsiveness to Myelin through Nogo-66 Receptor 1 Cleavage

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