Key Points
-
There is a large unmet need for treatments for conditions such as spinal cord injury, traumatic head injury and stroke, which are all characterized by axonal damage in the central nervous system (CNS).
-
Promoting axon regrowth could be an attractive strategy to treat such injuries, but a key barrier has been the inability of CNS neurons to regenerate their axons after injury, which is generally attributed to the presence of growth inhibitors present in CNS myelin.
-
Three inhibitors of axonal regeneration have been identified in CNS myelin: Nogo, myelin-associated glycoprotein (Mag) and oligodendrocyte myelin glycoprotein (Omgp). These myelin proteins induce growth cone collapse and inhibit neurite outgrowth.
-
Recently, it has been demonstrated that these inhibitory molecules all act through the Nogo receptor (NgR), making NgR a focal point for modulating axonal regrowth.
-
In this review, we discuss recent advances in the understanding of the biological role of NgR and the relevance of these findings to a novel drug discovery strategy of promoting CNS axonal regrowth for treating CNS injuries.
Abstract
Axonal damage is a key pathology in many injuries of the central nervous system (CNS), such as spinal cord injury, traumatic brain injury and stroke, as well as in multiple sclerosis. An attractive drug discovery strategy to treat such conditions is to search for agents that promote CNS axonal regeneration. Historically, limited knowledge concerning the basis of poor CNS regeneration has precluded a rational drug discovery approach for promoting axonal regeneration. The recent identification of the Nogo receptor, which interacts with inhibitory myelin protein, established the crucial role of this molecular pathway in mediating the inhibitory effects of CNS myelin. This provides an unprecedented opportunity to manipulate adult CNS axonal regeneration. The development of therapeutics targeting the Nogo receptor has the potential to promote functional recovery and reverse the devastating consequences of CNS injuries.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Berkowitz, M., O'Leary, P. K., Kruse, D. L. & Harvey, C. Spinal Cord Injury: An Analysis of Medical and Social Costs. (Demos Medical, New York, 1998).
CDC. Traumatic brain injury in the United States: a report to Congress. Atlanta, Georgia: US Department of Health and Human Services, CDC, National Center for Injury Prevention and Control (1999).
Leary, M. C. & Saver, J. L. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc. Dis. 16, 280–285 (2003).
Peterson, J. W., Bo, L., Mork, S., Chang A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001).
Ramón y Cajal, S. Degeneration and Regeneration of the Nervous System (Hafner, New York, 1928).
Caroni, P. & Schwab, M. E. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading.J. Cell Biol. 106, 1281-1288 (1988).
Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).
GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000).
Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000). References 7–9 are three simultaneous landmark papers describing the molecular identification of NogoA. This report also identified the IN-1 antigen as NogoA.
Mukhopadhyay, G., Doherty, P., Walsh, F. S., Crocker, P. R. & Filbrin, M. T. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767 (1994). An important report on the first identification of MAG as a myelin-derived inhibitor of neurite growth.
McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994).
Mikol, D. D. & Stefansson, K. A phosphatidylinositol-linked peanut agglutinin-binding glypcoprotein in central nervous system myelin and on oligodendrocytes. J. Cell Biol. 106, 1273–1279 (1988).
Mikol, D. D. et al. Structure and chromosomal localization of the gene for the oligodendrocyte-myelin glycoprotein. J. Cell Biol. 111, 2673–2679 (1990).
Kottis, V. et al. Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. J. Neurochem. 82, 1566–1569 (2002).
Caroni, P. & Schwab, M. E. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96 (1988). A landmark paper describing the generation and activity of the anti-NogoA antibody.
Bregman, B. S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).
Merkler, D. et al. Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J. Neurosci. 21, 3665–3673 (2001).
Fiedler, M., Horn, C., Bandtlow, C., Schwab, M. E. & Skerra, A. An engineered IN-1 Fab fragment with improved affinity for the Nogo-A axonal growth inhibitor permits immunochemical detection and shows enhanced neutralizing activity. Protein Eng. 15, 931–941 (2002).
Brosamle, C., Huber, A. B., Fiedler M., Skerra, A. & Schwab, M. E. Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. J. Neurosci. 20, 8061–8068 (2000).
Basso, D. M., Beattie, M. S. & Bresnahan, J. C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21 (1995). This paper documents the behavioural rating scale for spinal cord injured rats.
Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001). A landmark study describing the molecular characterization of NgR.
GrandPre, T., Li, S. & Strittmatter, S. M. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551 (2002).
Huber, A. B. & Schwab, M. E. Nogo-A, a potent inhibitor of neurite outgrowth and regeneration. Biol. Chem. 381, 407–419 (2000).
Oertle, T. et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J. Neurosci. 23, 5393–5406 (2003).
Barton, W. A. et al. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. EMBO J. 22, 3291–3302 (2003). The authors reported the crystal structure of NgR (see also reference 33) and compare it with the predicted structures for NgR2/3 that do not bind myelin ligands.
Wang, X. et al. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J. Neurosci. 22, 5505–5515 (2002).
Liu, B. P., Fournier, A., GrandPre, T. & Strittmatter, S. M. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193 (2002).
Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002). References 27 and 28 report the identification of MAG as a second myelin ligand for NgR. The ability of NgR to bind to itself was also reported.
Wang, K. C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002). The documentation of OMgp as the third myelin-derived ligand for NgR. The authors also suggested that Nogo-66 and OMgp could compete for binding to NgR.
McGee, A. W. & Strittmatter, S. M. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends Neurosci. 26, 193–198 (2003).
Fournier, A. E., Gould, G. C., Liu, B. P. & Strittmatter, S. M. Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. J. Neurosci. 22, 8876–8883 (2002).
Wang, K. C., Kim, J. A., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002). The authors reported p75 to be a co-receptor for NgR, mediating the effects of NogoA, MAG and OMgp.
He, X. L. et al. Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Neuron 38, 177–185 (2003). The authors reported the crystal structure of NgR and postulated that several regions on NgR might be important for ligand binding. See also reference 25.
Pignot, V. et al. Characterization of two novel proteins, NgRH1 and NgRH2, structurally and biochemically homologous to the Nogo-66 receptor. J. Neurochem. 85, 717–728 (2003). The authors reported on two homologous proteins of NgR.
Li, W. et al. Neutralization of NgR1 is sufficient for promoting rat DRG neurite outgrowth against CNS myelin inhibition. 33rd Ann. Meeting Soc. Neurosci. (2003).
Mullen, C. et al. Characterization of a monoclonal anti-Nogo receptor antibody. 32nd Ann. Meeting Soc. Neurosci. Program no. 333.3 (2002).
Choi, E. et al. Characterization of an anti-Nogo receptor Fab that disrupts NogoA/Nogo receptor interaction. 32nd Ann. Meeting Soc. Neurosci. Program no. 333.1 (2002).
Li, W. et al. Neutralization of myelin-associated Nogo-A by Nogo receptor–Fc fusion protein. 32nd Ann. Meeting Soc. Neurosci. Program no. 333.2 (2002).
Wong, S. T. et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5, 1302–1308 (2002).
Yamashita, T., Tucker, K. L. & Barde, Y. A. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).
Yamashita, T. & Tohyama, M. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nature Neurosci. 6, 461–467 (2003).
Yamashita, T., Higuchi, H. & Tohyama, M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570 (2002).
Beattie, M. S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).
Dechant, G. & Barde, Y. A. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nature Neurosci. 5, 1131–1136 (2002).
Cosgaya, J. M., Chan, J. R. & Shooter, E. M. The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298, 1245–1248 (2002).
Jin, Z. & Strittmatter, S. M. Rac1 mediates collapsin-1-induced growth cone collapse. J. Neurosci. 17, 6256–6263 (1997).
Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577 (2002).
Fournier, A. E., Takizawa, B. T. & Strittmatter, S. M. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416–1423 (2003).
Niederost, B., Oertle, T., Fritsche, J., McKinney, R. A. & Bandtlow, C. E. Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J. Neurosci. 22, 10368–10376 (2002).
Lehmann, M. et al. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547 (1999).
Monnier, P. P., Sierra, A., Schwab, J. M., Henke-Fahle, S. & Mueller, B. K. The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell Neurosci. 22, 319–330 (2003).
Li, S. & Strittmatter, S. M. Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J. Neurosci. 23, 4219–4227 (2003). An important paper documenting the in vivo efficacy of the NgR antagonist, NEP1-40 peptide in promoting neurite sprouting and functional recovery in hemi-transected rats. Furthermore, both systemic administration and delayed administration of the peptide by seven days resulted in similar recovery and sprouting.
Papadopoulos, C. M. et al. Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat. Ann. Neurol. 51, 433–441 (2002). The first documentation of the use of Nogo/NgR pathway reagents for promoting functional recovery in a rat model of stroke.
Emerick, A. J., Neafsey, E. J., Schwab, M. E. & Kartje, G. L. Functional reorganization of the motor cortex in adult rats after cortical lesion and treatment with monoclonal antibody IN-1. J. Neurosci. 23, 4826–4830 (2003).
Wiessner, C. et al. Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J. Cereb. Blood Flow Metab. 23, 154–165 (2003).
Schnell, L., Schneider, R., Kolbeck, R., Barde, Y. A. & Schwab, M. E. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173 (1994).
Grill, R., Murai, K., Blsch, A., Gage, F. H. & Tuszynski, M. H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572 (1997). This paper describes a cell therapy approach for delivering recombinant neurotrophin-3 to spinal cord lesions that resulted in partial functional recovery. There is a well-written description of the relative roles of different spinal projections in locomotion.
Benowitz, L. I., Goldberg, D. E., Madsen, J. R., Soni, D. & Irwin, N. Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc. Natl Acad. Sci. USA 96, 13486–90 (1999).
Bavetta, S., Hamlyn, P. J., Burnstock, G., Lieberman, A. R. & Anderson, P. N. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp. Neurol. 158, 382–393 (1999).
Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 589–590 (2002).
Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).
Filbrin, M. T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nature Rev. Neurosci. 4, 703–713 (2003).
Cui, Q., Yip, H. K., Zhao, R. C., So, K. F. & Harvey, A. R. Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol. Cell Neurosci. 22, 49–61 (2003).
Hunt, D., Mason, M. R. J., Campbell, G., Coffin, R. & Anderson, P. N. Nogo recptor mRNA expression in intact and regenerating CNS neurons. Mol. Cell Neurosci. 20, 537–552 (2002).
Author information
Authors and Affiliations
Corresponding author
Glossary
- MYELIN SHEATH
-
The sheets of membranes derived from oligodendrocytes wrapping around nerve fibres in the central nervous system that provide trophic support and facilitate nerve impulse transmission. Detergent extraction of these membranes yields a protein mixture named myelin that inhibits neurite outgrowth and induces growth cone collapse.
- GROWTH CONE COLLAPSE
-
The tips of the growing axons and neurites are characterized by a fan-shaped structure (laminopodia) accompanied by several outgrowths (filapodia). Together, these structures form the growth cone of an axon or neurite. When a growing axon comes into contact with an unfavourable environment, the growth cone changes in morphology, shrinking to form a stump. This phenomenon is generally described as growth cone collapse, and is indicative of halted neurite growth.
- BBB SCORE
-
A 21-point scale of behavioural scoring for assessment of open-field locomotion abilities.
- LEUCINE-RICH REPEATS
-
Small protein domains comprising ∼23 amino-acid residues that are characterized by the dominant presence of leucine residues. Examples include NgR, NgRh1, NgRh2 and OMgp.
- DORSAL ROOT GANGLION
-
DRG. Groups of sensory neuron cell bodies that correspond to a particular level of the spinal cord. These neurons are frequently used in culture assays to assess neurite outgrowth or growth cone collapse.
- INTRATHECAL DELIVERY
-
Direct delivery of a molecule via a catheter or needle inserted under the dura of the spinal cord, thereby bypassing the blood–brain barrier. The molecule subsequently becomes distributed via the cerebral spinal fluid to different parts of the spinal cord and can reach the brain.
- BDA TRACING
-
Biotinylated dextran acetate (BDA) is a stable, non-metabolized, low-molecular-mass compound that after injection into the motor cortex is transported along the axons. The molecule can be detected in tissue sections using appropriately tagged strepavidin (for example, conjugated with horse radish peroxidase) for labelling nerve fibres.
Rights and permissions
About this article
Cite this article
Lee, D., Strittmatter, S. & Sah, D. Targeting the Nogo Receptor to Treat Central Nervous System Injuries. Nat Rev Drug Discov 2, 872–879 (2003). https://doi.org/10.1038/nrd1228
Issue Date:
DOI: https://doi.org/10.1038/nrd1228
This article is cited by
-
Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury
Communications Biology (2018)
-
Nogo/RTN4 isoforms and RTN3 expression protect SH-SY5Y cells against multiple death insults
Molecular and Cellular Biochemistry (2013)
-
TAT-Mediated Protein Transduction of Nogo Extracellular Peptide 1-40 and its Biological Activity
Cellular and Molecular Neurobiology (2009)
-
Genetic Manipulation of Neural Stem Cells for Transplantation into the Injured Spinal Cord
Cellular and Molecular Neurobiology (2007)
-
Bone Marrow Stem Cells and Polymer Hydrogels—Two Strategies for Spinal Cord Injury Repair
Cellular and Molecular Neurobiology (2006)