High Molecular Weight Protein of Human Central Nervous System Myelin Inhibits Neurite Outgrowth: an Effect which can be Neutralized by the Monoclonal Antibody IN‐1

Spillmann, Adrian A.; Amberger, Verena R.; Schwab, Martin E.

doi:10.1111/j.1460-9568.1997.tb01631.x

Cited by 44 publications

(31 citation statements)

References 37 publications

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“…The conservation of the C-terminal domain within the reticulon family suggests a particularly crucial role for the transmembrane segment of the protein, possibly connected to the receptor-binding domain it contains. Although the inhibitory effects of the Nogo protein and its receptor on neurite outgrowth in vitro have been well established (Spillmann et al, 1997;Chen et al, 2000;GrandPre et al, 2000), the underlying physiological role of the protein in vivo remains to be determined. We show here that Nogo-A is developmentally regulated both in chick and human embryos, and it is first detected at stages of development when the chick spinal cord is able to regenerate.…”

Section: Discussionmentioning

confidence: 99%

“…These factors include chondroitin sulphate proteoglycans (Zuo et al, 1998;Bradbury et al, 2002), myelin-associated glycoprotein (McKerracher et al, 1994;Mukhopadhyay et al, 1994), and Nogo (Varga et al, 1995). Neutralization of Nogo function with specific antibodies appears to enhance axonal extension in vitro (Spillmann et al, 1997) and in vivo (Brosamle et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

O’Neill¹,

Whalley²,

Ferretti³

2004

Developmental Dynamics

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Antibodies to the myelin protein Nogo increase axonal regrowth after central nervous system injury. We have investigated whether Nogo expression contributes to loss of regenerative potential during development by using chick embryos, which regenerate their spinal cord until embryonic day (E) 13, when myelination begins. We show that Nogo-A and the Nogo receptor (NgR) are developmentally regulated both in chick and human embryos, are first detected at developmental stages when the chick spinal cord regenerates, and are not down-regulated after injury at permissive stages for regeneration. Therefore, expression of Nogo-A and NgR in pre-E13 chick spinal cords is not sufficient to inhibit regeneration. Nogo-A expression in the chick early embryo is primarily observed in axons, whereas NgR is mainly located on neuronal cell bodies, both in spinal cord and eye, and in striated muscle including the heart. With the onset of myelination, there is down-regulation of Nogo-A expression in neurons. Therefore, loss of regenerative potential might be linked to changes in its cellular localization. The possibility that only Nogo expressed in mature oligodendrocytes can exercise inhibitory effects would reconcile the lack of inhibition we observe in developing chick spinal cords before the onset of myelination with evidence from other laboratories on the inhibitory effects of Nogo in mature central nervous system. The distinctive and complementary patterns of Nogo-A and NgR expression and their conservation throughout evolution support the view that Nogo signaling represents a key pathway in nervous system and striated muscle development. Its putative role in target innervation and establishment of neural circuitry is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

O’Neill¹,

Whalley²,

Ferretti³

2004

Developmental Dynamics

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“…Active fractions after gel filtration (s-pool 1) were separated by 6% SDS-PAGE (10 ϫ 24 ϫ 0.01 cm gel) under reducing conditions and low constant power (2 watts/gel) to a total of 2500 Vh. Bands and gel regions were identified after Coomassie Blue staining (0.1% w/v R250 in 50% methanol and 10% acetic acid), cut out, and extracted in 800 l of gel elution buffer (0.5% (w/v) CHAPS, 20 mM Tris-Cl, pH 8.0, 10 mM EDTA, pH 8.0, 2.5 mM iodacetamide, 1 mM phenylmethylsulfonyl fluoride, 0.1 g/ml aprotinin, 1 g/ml leupeptin, 1 g/ml pepstatin A) for at least 48 h at 4°C (30).…”

Section: Methodsmentioning

confidence: 99%

“…Proteins eluted from gel slices containing molecules with an apparent molecular mass of 35 and 250 kDa (SDS-PAGE) showed a very potent inhibitory activity (23,24). A monoclonal antibody (mAb IN-1), which has been raised against rat , neutralizes the neurite growth inhibitory property of differentiated oligodendrocytes and [24][25][26][27][28][29][30]. Immunoprecipitation of CNS myelin proteins by the mAb IN-1 removed more than 50% of inhibitory substrate properties (25,31).…”

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confidence: 99%

Identification and Characterization of a Bovine Neurite Growth Inhibitor (bNI-220)

Spillmann

Bandtlow

Lottspeich³

et al. 1998

Journal of Biological Chemistry

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143

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The poor axonal regeneration that follows lesions of the central nervous system (CNS) is crucially influenced by the local CNS tissue environment through which neurites have to grow. In addition to an inhibitory role of the glial scar, inhibitory substrate effects of CNS myelin and oligodendrocytes have been demonstrated. Several proteins including NI-35/250, myelin-associated glycoprotein, tenascin-R, and NG-2 have been described to have neurite outgrowth inhibitory or repulsive properties in vitro. Antibodies raised against NI-35/250 (monoclonal antibody IN-1) were shown to partially neutralize the growth inhibitory effect of CNS myelin and oligodendrocytes, and to result in long distance fiber regeneration in the lesioned adult mammalian CNS in vivo. We report here the purification of a myelin protein to apparent homogeneity from bovine spinal cord which exerts a potent neurite outgrowth inhibitory effect on PC12 cells and chick dorsal root ganglion cells, induces collapse of growth cones of chick dorsal root ganglion cells, and also inhibits the spreading of 3T3 fibroblasts. These activities could be neutralized by the monoclonal antibody IN-1. The purification procedure includes detergent solubilization, anion exchange chromatography, gel filtration, and elution from high resolution SDSpolyacrylamide gel electrophoresis. The active protein has a molecular mass of 220 kDa and an isoelectric point between 5.9 and 6.2. Its inhibitory activity is sensitive to protease treatment and resists harsh treatments like 9 M urea or short heating. Glycosylation is, if present at all, not detectable. Microsequencing resulted in six peptides and strongly suggests that this proteins is novel.Neurite growth in the mammalian CNS 1 ceases at the end of the developmental period. Although CNS neurons maintain some ability to rearrange their axonal and dendritic arbors in the adult brain, regeneration of severed CNS axons over long distances is absent. Transplantations of peripheral nerve explants into various parts of the brain and spinal cord revealed that the lack of regeneration is not primarily due to intrinsic properties of CNS neurons but is instead dependent on the microenvironment encountered by the regenerating fibers (1, 2); CNS axons were able to grow over long distances in the peripheral nerve segments, but ceased to grow as they entered the CNS tissue again (2).Several lines of evidence suggest that the presence of inhibitory factors rather than the lack of growth promoting molecules is responsible to the non-conducive properties of CNS tissue in adult vertebrates (for review, see Ref. 3). In vitro experiments demonstrated that adult optic nerve explants were not invaded by neurites, although high amounts of neurotrophic factors were provided (4). Similarly, cryostat sections of adult CNS tissue were shown to be non-permissive substrates for neurite outgrowth, especially the densely myelinated areas (5-9). Differentiated oligodendrocytes in culture and CNS myelin exerted a strong inhibitory effect on adhesion and ou...

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“…Following spinal cord severance, a complex pathophysiological cascade ensues that inhibits potential axonal regrowth and forms scar tissue (Figures 3d-g). 38 It is also important to note that there is evidence to support native locomotive abilities in animals with a fully transected spinal cord because of inherent spinal cord circuitry. 39 Thus, in order to assure that natural or intervention-based recovery is truly determined by the Spinal cord injury models T Cheriyan et al transection, the cord should be retransected to observe loss of regained function.…”

Section: Full Transectionmentioning

confidence: 99%

Spinal cord injury models: a review

et al. 2014

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Background: Animal spinal cord injury (SCI) models have proved invaluable in better understanding the mechanisms involved in traumatic SCI and evaluating the effectiveness of experimental therapeutic interventions. Over the past 25 years, substantial gains have been made in developing consistent, reproducible and reliable animal SCI models. Study design: Review. Objective: The objective of this review was to consolidate current knowledge on SCI models and introduce newer paradigms that are currently being developed. Results: SCI models are categorized based on the mechanism of injury into contusion, compression, distraction, dislocation, transection or chemical models. Contusion devices inflict a transient, acute injury to the spinal cord using a weight-drop technique, electromagnetic impactor or air pressure. Compression devices compress the cord at specific force and duration to cause SCI. Distraction SCI devices inflict graded injury by controlled stretching of the cord. Mechanical displacement of the vertebrae is utilized to produce dislocation-type SCI. Surgical transection of the cord, partial or complete, is particularly useful in regenerative medicine. Finally, chemically induced SCI replicates select components of the secondary injury cascade. Although rodents remain the most commonly used species and are best suited for preliminary SCI studies, large animal and nonhuman primate experiments better approximate human SCI. Conclusion: All SCI models aim to replicate SCI in humans as closely as possible. Given the recent improvements in commonly used models and development of newer paradigms, much progress is anticipated in the coming years. Spinal Cord (2014) 52, 588-595; doi:10.1038/sc.2014.91; published online 10 June 2014 INTRODUCTIONSpinal cord injury (SCI) models have proved indispensible not only for investigating the efficacy of therapeutic interventions but also for better understanding the molecular pathways involved. SCI models have evolved significantly over the past century since Allen developed the first weight-drop contusion model in 1911. 1 SCI models aim to recreate features of human SCI as closely as possible. These models vary in terms of the animal utilized, site of injury infliction and injury mechanism.Rats are used most commonly in preliminary studies as they are relatively inexpensive, readily available and have demonstrated similar functional, electrophysiological, and morphological outcomes to humans following SCI. 2 Mice are particularly useful for genetic studies. 3 Nonhuman primate SCI models-including marmosets, macaques and squirrel monkeys-better approximate human SCI than rodent models, and they accommodate assessment of multiple recovery variables and rehabilitative therapy. 4 New world primates like marmosets confer advantages over old world primates as they are smaller, easier to handle, have a higher breeding efficiency and can be bred in experimental colonies. SCI models that incorporate large animals-such as pigs or dogs-can also be used when it is important for furth...

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High Molecular Weight Protein of Human Central Nervous System Myelin Inhibits Neurite Outgrowth: an Effect which can be Neutralized by the Monoclonal Antibody IN‐1

Cited by 44 publications

References 37 publications

Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

Identification and Characterization of a Bovine Neurite Growth Inhibitor (bNI-220)

Spinal cord injury models: a review

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