The membrane protein Nogo-A is a major player in the neurite growth-inhibitory and regeneration-inhibitory effects exerted by myelin in the mammalian brain and spinal cord. In the injured CNS, neutralization or blockade of Nogo-A enhances regeneration, compensatory fibre sprouting and functional recovery. In the intact nervous system, a number of physiological functions of Nogo proteins have been recently discovered, as discussed in this Review.
Nogo proteins and the related reticulon (RTN)1-3 proteins consist of a highly conserved, 200-amino acid carboxy-terminal RTN domain and non-homologous amino-terminal extensions of various lengths. The neurite growth-inhibitory protein Nogo-A appeared in evolution for the first time in frogs and is present in all higher vertebrates. Two active sites are present; a Nogo-A-specific domain and a 66-amino acid domain that lies between the transmembrane and intramembrane parts of the RTN domain. Nogo-A is highly enriched in the nervous system, in oligodendrocytes and myelin at adult stages, and in neurons and precursor cells during development. The short proteins Nogo-B and Nogo-C are not inhibitory and occur in various tissues, including the nervous system.
Two binding sites are currently known for the Nogo-66 sequence, the Nogo receptor 1 (NgR1) and the membrane protein paired immunoglobulin-like receptor B (PIRB). Both receptors also interact with other ligands, however. The receptor for the Nogo-A specific active site remains to be characterized. Rho activation followed by destabilizing effects on the cytoskeleton are obligatory steps in the postreceptor signalling and effector pathway that leads to the collapse of neurite growth cones. Several additional proteins are associated with what is probably a multisubunit receptor complex for Nogo-A.
Nogo-B, by interaction with a Nogo-B receptor (NGBR), influences vascular endothelial cells and smooth muscle cells, which hyperproliferate after vascular lesions in Nogo-A and Nogo-B double knockout mice. The function of Nogo-C is currently still unknown.
During CNS development, Nogo-A and its receptors are expressed in cortical precursors and affect their migration. Many projection neurons in the central and peripheral nervous systems express Nogo-A during axonal outgrowth; its neutralization or knockout enhances axonal fasciculation and influences branching. NgR1 and the shorter Nogo forms also have guidance and fasciculation functions in zebrafish, a lower vertebrate.
In the adult CNS, oligodendrocyte and myelin Nogo-A suppresses the growth programme of adult neurons, probably by a retrograde action on the cell bodies. Locally, neurite growth is dampened by the growth cone collapsing actions of Nogo-A. Nogo-A thus acts as a stabilizer of the adult CNS neuronal network and wiring. Ablation of Nogo-A or NgR1 accordingly enhances plastic rearrangements of CNS connections, extending the so-called 'critical period' far into adult ages, for example, for visual cortex plasticity. The schizophrenia-like behaviour of Nogo-A knockout mice and the associations found between psychiatric disorders and mutations in the genes encoding Nogo or NgR1 may be based on similar functions.
In addition to its cell surface expression, high amounts of Nogo are also present intracellularly. In neurons, its interaction with β-secretase points to a role in the regulation of amyloid precursor protein (APP) processing. Manipulations of Nogo have indicated a structural role for Nogo in the endoplasmic reticulum (ER) and the nuclear membrane. Interactions with proteins involved in cell survival and apoptosis have also been observed.
Various approaches aimed at suppressing Nogo-A or NgR1 actions have been used following injury of the adult spinal cord or brain. Acute functional suppression and, with more variable effects, chronic genetic deletion enhance regenerative sprouting and growth of various CNS tract systems. In addition, spared fibre systems have shown enhanced compensatory sprouting; both these processes were associated with substantial improvements of the behavioural recovery of lost functions in rodents and monkeys. These results illustrate the important growth-suppressive role of Nogo-A in the adult mammalian CNS.
The membrane protein Nogo-A was initially characterized as a CNS-specific inhibitor of axonal regeneration. Recent studies have uncovered regulatory roles of Nogo proteins and their receptors — in precursor migration, neurite growth and branching in the developing nervous system — as well as a growth-restricting function during CNS maturation. The function of Nogo in the adult CNS is now understood to be that of a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury. In addition, Nogo proteins interact with various intracellular components and may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival.
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Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).
Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen form 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).
Oertle, T. et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J. Neurosci. 23, 5393–5406 (2003).
Oertle, T. & Schwab, M. E. Nogo and its paRTNers. Trends Cell Biol. 13, 187–194 (2003).
Oertle, T., Huber, C., van der Putten, H. & Schwab, M. E. Genomic structure and functional characterisation of the promoters of human and mouse nogo/rtn4. J. Mol. Biol. 325, 299–323 (2003).
Li, M. & Song, J. The N- and C-termini of the human Nogo molecules are intrinsically unstructured: bioinformatics, CD, NMR characterization, and functional implications. Proteins 68, 100–108 (2007).
Dodd, D. A. et al. Nogo-A, -B and -C are found on the cell surface and interact together in many different cell types. J. Biol. Chem. 280, 12494–12502 (2005).
Oertle, T., Klinger, M., Stuermer, C. A. O. & Schwab, M. E. A reticular rhapsody: phylogenic evolution and nomenclature of the RTN/Nogo gene family. FASEB J. 17, 1238–1247 (2003).
Diekmann, H. et al. Analysis of the reticulon gene family demonstrates the absence of the neurite growth inhibitor Nogo-A in fish. Mol. Biol. Evol. 22, 1635–1648 (2005).
Schweigreiter, R. The natural history of the myelin-derived nerve growth inhibitor Nogo-A. Neuron Glia Biol. 4, 83–89 (2008).
Klinger, M. et al. Identification of two nogo/rtn4 genes and analysis of Nogo-A expression in Xenopus laevis. Mol. Cell. Neurosci. 25, 205–216 (2004).
Ferretti, P., Zhang, F. & O'Neill, P. Changes in spinal cord regenerative ability through phylogenesis and development: lessons to be learnt. Dev. Dyn. 226, 245–256 (2003).
Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).
Hu, F. et al. Nogo-A interacts with the Nogo-66 receptor throuth multiple sites to create an isoform-selective subnanomolar agonist. J. Neurosci. 25 5298–5304 (2005).
GrandPre, T., Li, S. & Strittmatter, S. M. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551 (2002).
Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (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).
Venkatesh, K. et al. The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein. J. Neurosci. 25, 808–822 (2005).
Park, J. H. et al. Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-β plaque deposition. J. Neurosci. 26, 1386–1395 (2006).
Zhang, L. et al. Identification of BLyS (B lymphocyte stimulator), a non-myelin-associated protein, as a functional ligand for Nogo-66 receptor. J. Neurosci. 29, 6348–6352 (2009).
Thomas, R. et al. LGI1 is a Nogo receptor 1 ligand that antagonizes myelin-based growth inhibition. J. Neurosci. 30, 6607–6612 (2010).
Atwal, J. K. et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322, 967–970 (2008).
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).
Chivatakarn, O., Kaneko, S., He, Z., Tessier-Lavigne, M. & Giger, R. J. The Nogo-66 receptor NgR1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors. J. Neurosci. 27, 7117–7124 (2007).
Takei, Y. Phosphorylation of Nogo receptors suppresses Nogo signaling, allowing neurite regeneration. Sci. Signal 2, ra14 (2009).
Lee, J. K., Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 24, 6209–6217 (2004).
Kim, J. E., Liu, B. P., Park, H. J. & Strittmatter, S. M. Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron 44, 439–451 (2004).
Zheng, B. et al. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc. Natl Acad. Sci. USA 102, 1205–1210 (2005).
Fischer, D., He, Z. & Benowitz, L. I. Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J. Neurosci. 24, 1651 (2004).
Syken, J., Grandpre, T., Kanold, P. O. & Shatz, C. J. PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795–1800 (2006).
McGee, A. W., Yang, Y., Fischer, Q. S., Daw, N. W. & Strittmatter, S. M. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226 (2006). This paper shows that the developmental plasticity in the well-known paradigm of visual cortex ocular dominance columns is restricted at the end of the critical period by mechanisms involving NgR, and Nogo-A and Nogo-B.
Nash, M., Pribiag, H., Fournier, A. E. & Jacobson, C. Central nervous system regeneration inhibitors and their intracellular substrates. Mol. Neurobiol. 40, 224–235 (2009). A recent review on the intracellular pathways, in particular RHOA signalling, that have key roles in Nogo signalling.
Spencer, T., Domeniconi, M., Cao, Z. & Filbin, M. T. New roles for old proteins in adult CNS axonal regeneration. Curr. Opin. Neurobiol. 13, 133–139 (2003).
Yiu, G. & He, Z. Glial inhibition of CNS axon regeneration. Nature Rev. Neurosci. 7, 617–627 (2006).
Shao, Z. et al. TAJ/TROY, an orphan TNR receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 45, 353–359 (2005).
Park, J. B. et al. A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron 45, 345–351 (2005).
Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature Neurosci. 7, 221–228 (2004).
Ji, B. et al. LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. Mol. Cell. Neurosci. 33, 311–320 (2006).
Lv, J. et al. Passive immunization with LINGO-1 polyclonal antiserum afforded neuroprotection and promoted functional recovery in a rat model of spinal cord injury. Neuroimmunomodulation 17, 270–278 (2010).
Okafuji, T. & Tanaka, H. Expression patern of LINGO-1 in the developing nervous system of the chick embryo. Gene Expr. Patterns 6, 57–62 (2005).
Barrette, B., Vallieres, N., Dube, M. & Lacroix, S. Expression profile of receptors for myelin-associated inhibitors of axonal regeneration in the intact and injured mouse central nervous system. Mol. Cell. Neurosci. 34, 519–538 (2007).
Hu, F. & Strittmatter, S. M. The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. J. Neurosci. 28, 1262–1269 (2008).
Koprivica, V. et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310, 106–110 (2005).
Grunewald, E., Kinnell, H. L., Porteous, D. J. & Thomson, P. A. GPR50 interacts with neuronal NOGO-A and affects neurite outgrowth. Mol. Cell. Neurosci. 42, 363–371 (2009).
Chao, M. V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature Rev. Neurosci. 4, 299–309 (2003).
Inestrosa, N. C. & Arenas, E. Emerging roles of Wnts in the adult nervous system. Nature Rev. Neurosci. 11, 77–86 (2010).
Rajasekharan, S. & Kennedy, T. E. The netrin protein family. Genome Biol. 10, 239 (2009).
Jackson, R. E. & Eickholt, B. J. Semaphorin signalling. Curr. Biol. 19, R504–R507 (2009).
Miao, R. Q. et al. Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proc. Natl Acad. Sci. USA 103, 10997–11002 (2006).
Acevedo, L. et al. A new role for Nogo as a regulator of vascular remodeling. Nature Med. 10, 382–388 (2004). The first demonstration of a role of Nogo proteins, in particular Nogo-B, in vascular endothelial cells and smooth muscle cells, and in blood vessel repair.
Harrison, K. D. et al. Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking. Cell Metab. 10, 208–218 (2009).
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).
Lehmann, M. et al. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547 (1999).
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).
Kubo, T., Yamaguchi, A., Iwata, N. & Yamashita, T. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther. Clin. Risk Manag. 4, 605–615 (2008).
Joset, A., Dodd, D. A., Halegoua, S. & Schwab, M. E. Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling. J. Cell Biol. 188, 271–285 (2010).
Deng, K. et al. Overcoming amino-Nogo-induced inhibition of cell spreading and neurite outgrowth by 12-O-tetradecanoylphorbol-13-acetate-type tumor promoters. J. Biol. Chem. 285, 6425–6433 (2010).
Bandtlow, C. E., Schmidt, M. F., Hassinger, T. D., Schwab, M. E. & Kater, S. B. Role of intracellular calcium in NI-35-evoked collapse of neuronal growth cones. Science 259, 80–83 (1993).
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).
Sivasankaran, R. et al. PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nature Neurosci. 7, 261–268 (2004).
Wang, B. et al. Nogo-66 promotes the differentiation of neural progenitors into astroglial lineage cells through mTOR–STAT3 pathway. PLoS ONE 3, e1856 (2008).
Gao, Y. et al. Nogo-66 regulates nanog expression through stat3 pathway in murine embryonic stem cells. Stem Cells Dev. 19, 53–60 (2010).
Hannila, S. S. & Filbin, M. T. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp. Neurol. 209, 321–332 (2008).
Yamashita, T. & Tohyama, M. The p75 receptor acts as a displacement factor that releases Rho from Rho–GDI. Nature Neurosci. 6, 461–467 (2003).
Hsieh, S. H. K., Ferraro, G. B. & Fournier, A. E. Myelin-associated inhibitors regulate cofilin phosphorylation and neuronal inhibition through LIM kinase and slingshot phosphatase. J. Neurosci. 26, 1006–1015 (2006).
Montani, L. et al. Neuronal Nogo-A modulates growth cone motility via Rho-GTP/LIMK1/cofilin in the unlesioned adult nervous system. J. Biol. Chem. 284, 10793–10807 (2009).
Cowan, C. W. et al. Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 46, 205–217 (2005).
Ibanez, C. F. Message in a bottle: long-range retrograde signaling in the nervous system. Trends Cell Biol. 17, 519–528 (2007).
Huber, A. B., Weinmann, O., Brösamle, C., Oertle, T. & Schwab, M. E. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J. Neurosci. 22, 3553–3567 (2002).
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).
O'Neill, P., Whalley, K. & Ferretti, P. Nogo and Nogo-66 receptor in human and chick: implications for development and regeneration. Dev. Dyn. 231, 109–121 (2004).
Caltharp, S. et al. Nogo-A induction and localization during chick brain development indicate a role disparate from neurite outgrowth inhibition. BMC Dev. Biol. 7, 32 (2007).
Mingorance-Le Meur, A., Zheng, B., Soriano, E. & Del Rio, J. A. Involvement of the myelin-associated inhibitor Nogo-A in early cortical development and neuronal maturation. Cereb Cortex 17, 2375–2386 (2007).
Mathis, C., Schroter, A., Thallmair, M. & Schwab, M. E. Nogo-A regulates neural precursor migration in the embryonic mouse cortex. Cereb Cortex 20, 2380–2390 (2010).
Wang, J., Chan, C. K., Taylor, J. S. & Chan, S. O. Localization of Nogo and its receptor in the optic pathway of mouse embryos. J. Neurosci. Res. 86, 1721–1733 (2008).
Wang, J., Wang, L., Zhao, H. & Chan, S. O. Localization of an axon growth inhibitory molecule Nogo and its receptor in the spinal cord of mouse embryos. Brain Res. 1306, 8–17 (2010).
Mingorance, A. et al. Regulation of Nogo and Nogo receptor during the development of the entorhino-hippocampal pathway and after adult hippocampal lesions. Mol. Cell Neurosci. 26, 34–49 (2004).
Wang, J., Chan, C. K., Taylor, J. S. & Chan, S. O. The growth-inhibitory protein Nogo is involved in midline routing of axons in the mouse optic chiasm. J. Neurosci. Res. 86, 2581–2590 (2008).
Josephson, A., Widenfalk, J., Widmer, H. W., Olson, L. & Spenger, C. Nogo mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury. Exp. Neurol. 169, 319–328 (2001).
Richard, M. et al. Neuronal expression of Nogo-A mRNA and protein during neurite outgrowth in the developing rat olfacotry system. Europ. J. Neurosci. 22, 2145–2158 (2005).
Hunt, D., Coffin, R. S., Prinjha, R. K., Campbell, G. & Anderson, P. N. Nogo-A expression in the intact and injured nervous system. Mol. Cell Neurosci. 24, 1083–1102 (2003).
Meier, S. et al. Molecular analysis of Nogo expression in the hippocampus during development and following lesion and seizure. FASEB J. 17, 1153–1155 (2003).
Lee, H. et al. Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength. J. Neurosci. 28, 2753–2765 (2008). The first comprehensive analysis of Nogo-A and its receptor components localized at synapses, and the possible role of NgR1 in synaptic plasticity
Liu, Y. Y., Jin, W. L., Liu, H. L. & Ju, G. Electron. microscopic localization of Nogo-A at the postsynaptic active zone of the rat. Neurosci. Lett. 346, 153–156 (2003).
Fry, E. J., Ho, C. & David, S. A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron 53, 649–662 (2007).
David, S., Fry, E. J. & Lopez-Vales, R. Novel roles for Nogo receptor in inflammation and disease. Trends Neurosci. 31, 221–226 (2008).
Pool, M. et al. Myelin regulates immune cell adhesion and motility. Exp. Neurol. 217, 371–377 (2009).
Bullard, T. A. et al. Identification of Nogo as a novel indicator of heart failure. Physiol. Genomics 32, 182–189 (2008).
Yu, J. et al. Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair. Proc. Natl Acad. Sci. USA 106, 17511–17516 (2009).
Magnusson, C., Svensson, A., Christerson, U. & Tagerud, S. Denervation-induced alterations in gene expression in mouse skeletal muscle. Eur. J. Neurosci. 21, 577–580 (2005).
Jokic, N. et al. Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Annals Neurology 57, 553–556 (2005).
Tozaki, H., Kawasaki, T., Takagi, Y. & Hirata, T. Expression of Nogo protein by growing axons in the developing nervous system. Molec. Brain Res. 104, 111–119 (2002).
Petrinovic, M. M. et al. Neuronal Nogo-A regulates neurite fasciculation, branching and extension in the developing nervous system. Development 137, 2539–2550 (2010). Using antibodies against Nogo-A or NgR as well as using Nogo-A knockout mice, this paper shows a role of Nogo-A expressed by developing neurons in neurite fasciculation and branching in vitro , and in chicken and mouse embryos.
Schwab, M. E. & Schnell, L. Channelling of developing rat corticospinal tract axons by myelin-associated neurite growth inhibitors. J. Neurosci. 11, 709–722 (1991).
Schwab, M. E. Nerve fiber regeneration after traumatic lesions of the CNS; progress and problems. Phil. Trans. R. Soc. B 331, 303–306 (1991).
Abdesselem, H., Shypitsyna, A., Solis, G. P., Bodrikov, V. & Stuermer, C. A. No Nogo-66- and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve. J. Neurosci. 29, 15489–15498 (2009).
Klinger, M. et al. Identification of Nogo-66 receptor (NgF) and homologous genes in fish. Mol. Biol. Evol. 21, 76–85 (2004).
Brosamle, C. & Halpern, M. E. Nogo–Nogo receptor signalling in PNS axon outgrowth and pathfinding. Mol. Cell Neurosci. 40, 401–409 (2009).
O'Brien, G. S. et al. Developmentally regulated impediments to skin reinnervation by injured peripheral sensory axon terminals. Curr. Biol. 19, 2086–2090 (2009). This paper shows that zebrafish embryos express short Nogo forms as well as NgR, which play a part in neurite growth and target reinnervation.
Pernet, V., Joly, S., Christ, F., Dimou, L. & Schwab, M. E. Nogo-a and myelin-associated glycoprotein differently regulate oligodendrocyte maturation and myelin formation. J. Neurosci. 28, 7435–7444 (2008).
Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nature Neurosci. 8, 745–751 (2005).
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).
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). One of three papers published in 1988 showing that CNS myelin is inhibitory for neurite growth, that a high molecular weight myelin protein ('NI-250', later called Nogo-A) is a key component of this activity and that it can be neutralized by antibodies. One of these antibodies was shown 2 years later to enhance long-distance regeneration in the injured rat spinal cord (see also references 103 and 105).
Schwab, M. E. & Caroni, P. Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro. J. Neurosci. 8, 2381–2393 (1988).
Maffei, A. & Turrigiano, G. The age of plasticity: developmental regulation of synaptic plasticity in neocortical microcircuits. Prog. Brain Res. 169, 211–223 (2008).
Hooks, B. M. & Chen, C. Critical periods in the visual system: changing views for a model of experience-dependent plasticity. Neuron 56, 312–326 (2007).
Schwegler, G., Schwab, M. E. & Kapfhammer, J. P. Increased collateral sprouting of primary afferents in the myelin-free spinal cord. J. Neurosci. 15, 2756–2767 (1995).
Kapfhammer, J. P. & Schwab, M. E. Inverse pattern of myelination and GAP-43 expression in the adult CNS: neurite growth inhibitors as regulators of neuronal plasticity? J. Comp. Neurol. 340, 194–206 (1994).
Craveiro, L. M. et al. Neutralization of the membrane protein Nogo-A enhances growth and reactive sprouting in established organotypic hippocampal slice cultures. Eur. J. Neurosci. 28, 1808–1824 (2008).
Park, K. J., Grosso, C. A., Aubert, I., Kaplan, D. R. & Miller, F. D. p75NTR-dependent, myelin-mediated axonal degeneration regulates neural connectivity in the adult brain. Nature Neurosci. 13, 559–566 (2010).
Aloy, E. M. et al. Synaptic destabilization by neuronal Nogo-A. Brain Cell Biol. 35, 137–156 (2006).
Karlen, A. et al. Nogo receptor 1 regulates formation of lasting memories. Proc. Natl Acad. Sci. USA 106, 20476–20481 (2009). The first demonstration that NgR is linked to specific aspects of memory in vivo.
Lai, K. O. & Ip, N. Y. Synapse development and plasticity: roles of ephrin/Eph receptor signaling. Curr. Opin. Neurobiol. 19, 275–283 (2009).
Yoshihara, Y., De Roo, M. & Muller, D. Dendritic spine formation and stabilization. Curr. Opin. Neurobiol. 19, 146–153 (2009).
Pasterkamp, R. J. & Giger, R. J. Semaphorin function in neural plasticity and disease. Curr. Opin. Neurobiol. 19, 263–274 (2009).
Willi, R. et al. Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes. J. Neurosci. 30, 556–567 (2010).
Novak, G., Kim, D., Seeman, P. & Tallerico, T. Schizophrenia and Nogo: elevated mRNA in cortex, in high prevalence of a homozygous CAA insert. Molecular Brain Res. 107, 183–189 (2002).
Tan, E. C., Chong, S. A., Wang, H., Lim, E. C. P. & Teo, Y. Y. Gender-specific association of insertion/deletoin polymorphisms in the nogo gene and chronic schizophrenia. Molec. Brain Res. 139 212–216 (2005).
Sinibaldi, L. et al. Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Hum. Mutat. 24, 534–535 (2004).
Hsu, R. et al. Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches. PLoS ONE 2, e1234 (2007).
Budel, S. et al. Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J. Neurosci. 28, 13161–13172 (2008). Some families affected with psychiatric diseases show mutations in NgR1 that affect its interaction with Nogo-66. Knock-in mice show weak schizophrenia-like phenotypes.
Lewis, D. A. & Levitt, P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002).
Teng, F. Y. & Tang, B. L. Cell autonomous function of Nogo and reticulons: the emerging story at the endoplasmic reticulum. J. Cell Physiol. 216, 303–308 (2008).
He, W. et al. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nature Med. 10, 959–965 (2004). The first demonstration that Rtn proteins, including Nogo, interact with BACE, suggesting that Nogo proteins could be physiological regulators of BACE activity and amyloid production.
Murayama, K. S. et al. Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein. Eur. J. Neurosci. 24, 1237–1244 (2006).
He, W. et al. Mapping of interaction domains mediating binding between BACE1 and RTN/Nogo proteins. J. Mol. Biol. 363, 625–634 (2006).
Park, J.H. et al. Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J. Neurosci. 26, 1386–1395 (2006).
Masliah, E. et al. Genetic deletion of Nogo/Rtn4 ameliorates behavioral and neuropathological outcomes in amyloid precursor protein transgenic mice. Neuroscience 169, 488–494 (2010).
Gil, V. et al. Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease. J. Neuropathol. Exp. Neurol. 65, 433–444 (2006).
Cheatwood, J. L., Emerick, A. J., Schwab, M. E. & Kartje, G. L. Nogo-A expression after focal ischemic stroke in the adult rat. Stroke 39, 2091–2098 (2008).
Yang, Y. S., Harel, N. Y. & Strittmatter, S. M. Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis. J. Neurosci. 29, 13850–13859 (2009).
Tagami, S., Eguchi, Y., Kinoshita, M., Takeda, M. & Tsujimoto, Y. A novel protein, RTN-xs, interacts with both Bcl-xL, and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Oncogene 19, 5736–5746 (2000).
Wan, Q. et al. Reticulon 3 mediates Bcl-2 accumulation in mitochondria in response to endoplasmic reticulum stress. Apoptosis 12, 319–328 (2007).
Li, Q. et al. Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. Oncogene 20, 3929–3936 (2001).
Oertle, T., Merkler, D. & Schwab, M. E. Do cancer cells die because of Nogo-B? Oncogene 22, 1390–1399 (2003).
Voeltz, G. K., Prinz, W. A., Shibata, Y., Rist, J. M. & Rapoport, T. A. A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124, 573–586 (2006). A demonstration of the role of Nogo proteins in structuring specific parts of the ER and its interaction with other ER membrane proteins that induce membrane curvature.
Kiseleva, E., Morozova, K. N., Voeltz, G. K., Allen, T. D. & Goldberg, M. W. Reticulon 4a/Nogo-A locates to regions of high membrane curvature and may have a role in nuclear envelope growth. J. Struct. Biol. 160, 224–235 (2007).
Anderson, D. J. & Hetzer, M. W. Reshaping of the endoplasmic reticulum limits the rate for nuclear envelope formation. J. Cell Biol. 182, 911–924 (2008).
Shibata, Y. et al. The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J. Biol. Chem. 283, 18892–18904 (2008).
Simonen, M. et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201–211 (2003).
Gonzenbach, R. R. & Schwab, M. E. Disinhibition of neurite growth to repair the injured adult CNS: focusing on Nogo. Cell. Mol. Life Sci. 65, 161–176 (2008). A review summarizing the various methods of Nogo-A blockade and its consequences for the treatment of spinal cord and brain injuries.
Rossignol, S., Schwab, M., Schwartz, M. & Fehlings, M. G. Spinal cord injury: time to move? J. Neurosci. 27, 11782–11792 (2007).
Xie, F. & Zheng, B. White matter inhibitors in CNS axon regeneration failure. Exp. Neurol. 209, 302–312 (2008).
Rowland, J. W., Hawryluk, G. W., Kwon, B. & Fehlings, M. G. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg. Focus 25, e2 (2008).
Cheatwood, J. L., Emerick, A. J. & Kartje, G. L. Neuronal plasticity and functional recovery after ischemic stroke. Top. Stroke Rehabil. 15, 42–50 (2008).
Liu, B. P., Cafferty, W. B., Budel, S. O. & Strittmatter, S. M. Extracellular regulators of axonal growth in the adult central nervous system. Phil. Trans. R. Soc. Lond. B 361, 1593–1610 (2006).
Fouad, K., Klusman, I. & Schwab, M. E. Regenerating corticospinal fibers in the marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1. Eur. J. Neurosci. 20, 2479–2482 (2004).
Freund, P. et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nature Med. 12, 790–792 (2006).
Freund, P. et al. Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates--re-examination and extension of behavioral data. Eur. J. Neurosci. 29, 983–996 (2009).
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).
Gordon, M. D. & Nusse, R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J. Biol. Chem. 281, 22429–22433 (2006).
Teng, K. K., Felice, S., Kim, T. & Hempstead, B. L. Understanding proneurotrophin actions: Recent advances and challenges. Dev. Neurobiol. 70, 350–359 (2010).
Moore, S. W., Tessier-Lavigne, M. & Kennedy, T. E. Netrins and their receptors. Adv. Exp. Med. Biol. 621, 17–31 (2007).
Ly, A. et al. DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1. Cell 133, 1241–1254 (2008).
Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).
Coon, H. et al. Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol. Psychiatry 3, 521–527 (1998).
Liu, H. et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc. Natl Acad. Sci. USA 99, 16859–16864 (2002).
Shaw, S. H. et al. A genome-wide search for schizophrenia susceptibility genes. Am. J. Med. Genet. 81, 364–376 (1998).
Willi, R., Aloy, E. M., Yee, B. K., Feldon, J. & Schwab, M. E. Behavioral characterization of mice lacking the neurite outgrowth inhibitor Nogo-A. Genes Brain Behav. 8, 181–192 (2009).
Braff, D. L., Geyer, M. A. & Swerdlow, N. R. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 156, 234–258 (2001).
Baruch, I., Hemsley, D. R. & Gray, J. A. Differential performance of acute and chronic schizophrenics in a latent inhibition task. J. Nerv. Ment. Dis. 176, 598–606 (1988).
Baptiste, D. C., Tighe, A. & Fehlings, M. G. Spinal cord injury and neural repair: focus on neuroregenerative approaches for spinal cord injury. Expert Opin. Investig. Drugs 18, 663–673 (2009).
Li, S. et al. Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble nogo-66 receptor promotes axonal sprouting and recovery after spinal cord. J. Neurosci. 24, 10511–10520 (2004).
Lee, J. K. et al. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron 66, 663–670 (2010).
Kim, J. E., Li, S., GrandPre, T., Qiu, D. & Strittmatter, S. M. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187–199 (2003).
Zheng, B. et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213–224 (2003).
Cafferty, W. B., Duffy, P., Huebner, E. & Strittmatter, S. M. MAG and OMgp synergize with Nogo-A to restrict axonal growth and neurological recovery after spinal cord trauma. J. Neurosci. 30, 6825–6837 (2010).
Dimou, L. et al. Nogo-A-deficient mice reveal strain-dependent differences in axonal regeneration. J. Neurosci. 26, 5591–5603 (2006).
Cafferty, W. B. & Strittmatter, S. M. The Nogo–Nogo receptor pathway limits a spectrum of adult CNS axonal growth. J. Neurosci. 26, 12242–12250 (2006).
Kempf, A., Montani, L., Petrinovic, M., Patrignani, A., Dimou, L., Schwab, M. E. EphrinA3 and ephrinB2 act as novel myelin-based neurite outgrowth inhibitors. Soc. Neurosci. Abstr. 411.9 (Chicago, IL, 17–21 October 2009).
Barbaric, I., Miller, G. & Dear, T. N. Appearances can be deceiving: phenotypes of knockout mice. Brief Funct. Genomic Proteomic 6, 91–103 (2007).
The author thanks his laboratory colleagues; in particular A. Buchli, A. Joset, V. Pernet, B. Tews and R. Willi for critically reading the manuscripts. The author's work is supported by grants from the Swiss National Science Foundation (3100AO-122,527/1), the National Center for Competence in Research 'Neural Plasticity & Repair' of the Swiss National Science Foundation, the Spinal Cord Consortium of the Christopher and Dana Reeve Foundation, several EU Framework 7 projects, and the International Foundation of Research in Paraplegia.
The author declares no competing financial interests.
- Compartmentalized cultures
Neurons are grown in the middle chamber of a three-chamber culture system. Their neurites are guided into the side chambers under a Teflon ring divider or through microfluidic channels. Neurites can be treated with substances and subsequently analysed separately from the cell bodies.
- Tangential migration
A mode of neuron migration that is non-radial. Most interneurons immigrate tangentially into the forebrain cortex from a proliferation zone in the basal ganglia region.
- Cortical plate
The upper part of the developing cerebral cortex, where neurons end their migration and start to assemble into the distinct neuronal layers that will form the future adult cortex.
A transient layer of cells in the fetal brain that lies beneath the cortical plate.
- Intermediate zone
A transient layer in the developing cortex through which neurons migrate on their way from the proliferative zone to the cortical plate. With maturation, this zone is replaced by the subcortical white matter.
Antisense oligonucleotides that block gene expression.
- Tubular ER
A major part of the endoplasmic reticulum (ER) of cells that is characterized by a tubular shape, as opposed to the flat ER cisterns that compose the nuclear membrane, or the Nissl bodies in synthetically highly active neurons.
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Schwab, M. Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci 11, 799–811 (2010). https://doi.org/10.1038/nrn2936
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