Alternative titles; symbols
HGNC Approved Gene Symbol: RTN4R
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:20,241,415-20,268,318 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 |
NOGO (604475) has been identified as a component of the central nervous system myelin that prevents axonal regeneration in the adult vertebrate central nervous system. Analysis of NogoA (amino-Nogo) has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes. The acidic amino terminus of NogoA is detected at the cytosolic face of cellular membranes and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury. Fournier et al. (2001) showed that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension but does not alter nonneuronal cell morphology. In contrast, a multivalent form of the N terminus of NogoA affects the morphology of both neurons and other cell types. Fournier et al. (2001) identified a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycosylphosphatidylinositol (GPI)-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human central nervous system (CNS) injury. The Nogo-66 receptor gene encodes a protein of 473 amino acids. The predicted protein contains a signal sequence followed by 8 leucine-rich-repeat (LRR) domains, a flanking LRR C-terminal domain that is cysteine rich, a unique region, and a GPI anchorage site. Subsequently, both Barton et al. (2003) and Pignot et al. (2003) showed that there is an N-terminal LRR domain preceding the 8 LRR domains. By Northern blot analysis Fournier et al. (2001) showed that expression of the Nogo-66 receptor is widespread in the brain; the areas richest in gray matter express the highest levels. Nogo-66 receptor mRNA is not detectable in white matter, where NogoA is expressed by oligodendrocytes. Northern blot analysis in mouse showed a single band of 2.3 kb in the adult brain, indicating that the isolated NgR clone is full length. Low levels of this mRNA are observed in heart and kidney but not in other peripheral tissues.
Fournier et al. (2001) used oligonucleotide primers based on the predicted NOGO receptor cDNA from the genomic sequence to amplify the human receptor from an adult brain cDNA library. The deduced protein shares 89% sequence identity with the mouse protein. The exons of the human NOGO receptor gene are separated by nearly 30 kb.
By Northern blot analysis, Pignot et al. (2003) found a 2.4-kb NGR transcript highly expressed in brain, moderately expressed in spleen and liver, and weakly expressed in skeletal muscle, lung, kidney, and placenta. A brain multitissue array revealed highest NGR expression in cerebellum, followed by several cortical areas, amygdala, hippocampus, and accumbens nucleus. Much weaker expression was detected in other brain regions examined. By digestion of NGR with phospholipase C, Pignot et al. (2003) confirmed that NGR has a GPI anchor, and sucrose density fractionation of transfected Chinese hamster ovary (CHO) cells demonstrated the association of human NGR with lipid rafts.
GrandPre et al. (2002) identified competitive antagonists of the NOGO receptor derived from amino-terminal peptide fragments of NOGO-66. The NOGO-66(1-40) antagonist peptide blocks NOGO-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that the NOGO receptor mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of the amino-terminal antagonist peptide to rats with midthoracic spinal cord hemisection resulted in significant axon outgrowth of the corticospinal tract, and improved functional recovery. Thus, GrandPre et al. (2002) concluded that NOGO-66 and the NOGO receptor have central roles in limiting axonal regeneration after CNS injury.
Wang et al. (2002) demonstrated that a GPI-anchored central nervous system myelin protein, oligodendrocyte-myelin glycoprotein (OMG; 164345), is a potent inhibitor of neurite outgrowth in cultured neurons. Like NOGOA (604475), OMGP contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity, Wang et al. (2002) screened an expression library and identified the NOGO receptor as a high affinity OMGP-binding protein. Cleavage of NOGO receptor and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMGP. Introduction of exogenous NOGO receptor confers OMGP responsiveness to otherwise insensitive neurons. Thus, OMGP is an important inhibitor of neurite outgrowth that acts through the NOGO receptor and its associated receptor complex. Wang et al. (2002) suggested that interfering with the OMGP/NOGO receptor pathway may allow lesioned axons to regenerate after injury in vivo.
Axonal regeneration in the adult CNS is limited by 2 proteins in myelin, Nogo and myelin-associated glycoprotein (MAG; 159460). The NOGO receptor (NgR) had been identified as an axonal GPI-anchored protein, whereas the MAG receptor had remained elusive. Liu et al. (2002) demonstrated that MAG binds directly, with high affinity, to NgR. Cleavage of GPI-linked proteins from axons protects growth cones from MAG-induced collapse, and dominant-negative NgR eliminates MAG inhibition of neurite outgrowth. MAG-resistant embryonic neurons were rendered MAG-sensitive by expression of NgR. MAG and Nogo-66 activate NgR independently and serve as redundant NgR ligands that may limit axonal regeneration after CNS injury.
Domeniconi et al. (2002) showed that MAG inhibits axonal regeneration through interaction with NgR. They demonstrated that MAG binds specifically to an NgR-expressing cell line in a GPI-dependent and sialic acid-independent manner. Consistent with a direct interaction of MAG and NgR, Domeniconi et al. (2002) observed that MAG precipitates NgR from NgR-expressing cells, dorsal root ganglia, and cerebellar neurons. Experiments blocking NgR from interacting with MAG prevented inhibition of neurite outgrowth by MAG. Using NgR-expressing cell cultures, the authors found that MAG and NOGO-66 compete directly for binding to NgR.
In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of NOGOA, OMGP, and MAG, exert their effects through the same NOGO receptor. The GPI-anchored nature of the NOGO receptor indicates the requirement for an additional transmembrane protein to transduce the inhibitory signals into the interior of responding neurons. Wang et al. (2002) demonstrated that p75 (NGFR; 162010), a transmembrane protein known to be a receptor for the neurotrophin family of growth factors, specifically interacts with the NOGO receptor. p75 is required for NOGO receptor-mediated signaling, as neurons from p75 knockout mice were no longer responsive to myelin or to any of the known NOGO receptor ligands. Blocking the p75-NOGO receptor interaction also reduced the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuated the same set of inhibitory activities, suggesting that p75 is a signal transducer of the Nogo receptor-p75 receptor complex. Wang et al. (2002) suggested that interfering with p75 and its downstream signaling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.
Wong et al. (2002) reported that p75(NTR) is a coreceptor for the NOGO receptor for MAG (159460) signaling. In cultured human embryonic kidney (HEK) cells expressing the NOGO receptor, p75(NTR) was required for MAG-induced intracellular calcium elevation. Coimmunoprecipitation showed an association of the NOGO receptor with p75(NTR) that could be disrupted by an antibody against p75(NTR), and extensive coexpression was observed in the developing rat nervous system. Furthermore, a p75(NTR) antibody abolished MAG-induced repulsive turning of Xenopus axonal growth cones and calcium elevation, both in neurons and in the NOGO receptor/p75(NTR)-expressing HEK cells.
Yu et al. (2004) observed that Ngr and p75 were colocalized in low-density membrane raft fractions of rat forebrain and cerebellum and in cultured cerebellar granule cells. Disruption of lipid rafts by a cholesterol-binding reagent reduced Nogo-66 signaling in the cultured cells. Yu et al. (2004) concluded that lipid rafts facilitate the interaction between Nogo receptor components.
By deletion analysis, Barton et al. (2003) showed that the binding of soluble fragments of NOGO, MAG, and NGR itself to cell-surface NGR required the entire LRR region (the N-terminal LRR, the 8 central LRRs, and the C-terminal LRR) of NGR, but not other portions of the protein.
He et al. (2003) reported the 1.5-angstrom crystal structure of NGR. They found that NGR adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues. A deep cleft at the C-terminal base of the LRR may play a role in the association of NGR with the p75 coreceptor.
Barton et al. (2003) reported the NGR structure to 2.3-angstrom resolution. They found that NGR has an elongated banana-like shape with approximate dimensions of 80 by 35 by 35 angstroms. It has low secondary structure content, consisting mostly of short beta strands that generate a long parallel beta sheet spanning the concave surface of the molecule.
Fournier et al. (2001) identified human sequence corresponding to the mouse NogoA receptor within a genomic cosmid sequence (GenBank AC007663) on chromosome 22q11.
Schizophrenia (181500) or schizoaffective disorders are rather common features in patients with DiGeorge/velocardiofacial syndrome (DGS, 188400/VCFS, 192430) as a result of 22q11.2 haploinsufficiency. Sinibaldi et al. (2004) evaluated the RTN4R gene, which maps within the DGS/VCFS critical region, as a potential candidate for schizophrenia susceptibility. They screened 120 unrelated Italian patients with schizophrenia for mutations in RTN4R using denaturing high performance liquid chromatography. Three mutant alleles were detected, including 2 missense changes (R119W, 605566.0001; R196H, 605566.0002) and 1 synonymous codon variant. The 2 schizophrenia patients with missense changes were strongly resistant to neuroleptic treatment at any dosage. Both missense changes were absent in 300 control subjects. Molecular modeling revealed that both changes lead to putative structural alterations of the native protein.
McGee et al. (2005) found that mutations in NgR affect cessation of ocular dominance plasticity. In NgR -/- mice, plasticity during the critical period was normal, but it continued abnormally such that ocular dominance at 45 or 120 days postnatal was subject to the same plasticity as at juvenile ages. Thus, physiologic Ngr signaling from myelin-derived Nogo, Mag, and Omgp (164345) consolidated the neural circuitry established during experience-dependent plasticity. McGee et al. (2005) concluded that after pathologic trauma, similar NgR signaling limits functional recovery and axonal regeneration.
In vitro, Zheng et al. (2005) found that neurite outgrowth from NgR-null mouse dorsal root ganglion or cerebellar granule neurons were inhibited by myelin or by a Nogo-66 substrate, similar to wildtype. Ngfr-deficient dorsal root ganglion neurons, but not cerebellar neurons, demonstrated somewhat less inhibition to myelin, suggesting that Ngfr works through a mechanism separate from NgR. In vivo, NgR-null and Ngfr-deficient mice did not show enhanced regeneration of corticospinal tract axons after spinal hemisection compared to wildtype. Zheng et al. (2005) concluded that NgR is not essential for mediating inhibitory signals from CNS myelin and does not play a central role in inhibition of axonal growth.
In an Italian patient with schizophrenia (181500), Sinibaldi et al. (2004) identified a 355C-T transition in the RTN4R gene that resulted in an arg119-to-trp (R119W) amino acid substitution. This patient was strongly resistant to neuroleptic treatment at any dosage. Molecular modeling revealed that this change led to putative structural alterations of the native protein.
In an Italian patient with schizophrenia (181500), Sinibaldi et al. (2004) identified a 587G-A transition in the RTN4R gene that resulted in an arg196-to-his (R196H) amino acid substitution. This patient was strongly resistant to neuroleptic treatment at any dosage. Molecular modeling revealed that this change led to putative structural alterations of the native protein.
Barton, W. A., Liu, B. P., Tzvetkova, D., Jeffrey, P. D., Fournier, A. E., Sah, D., Cate, R., Strittmatter, S. M., Nikolov, D. B. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. EMBO J. 22: 3291-3302, 2003. [PubMed: 12839991] [Full Text: https://doi.org/10.1093/emboj/cdg325]
Domeniconi, M., Cao, Z., Spencer, T., Sivasankaran, R., Wang, K. C., Nikulina, E., Kimura, N., Cai, H., Deng, K., Gao, Y., He, Z., Filbin, M. T. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35: 283-290, 2002. [PubMed: 12160746] [Full Text: https://doi.org/10.1016/s0896-6273(02)00770-5]
Fournier, A. E., GrandPre, T., Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409: 341-346, 2001. [PubMed: 11201742] [Full Text: https://doi.org/10.1038/35053072]
GrandPre, T., Li, S., Strittmatter, S. M. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417: 547-551, 2002. [PubMed: 12037567] [Full Text: https://doi.org/10.1038/417547a]
He, X. L., Bazan, J. F., McDermott, G., Park, J. B., Wang, K., Tessier-Lavigne, M., He, Z., Garcia, K. C. Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Neuron 38: 177-185, 2003. [PubMed: 12718853] [Full Text: https://doi.org/10.1016/s0896-6273(03)00232-0]
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. [PubMed: 12089450] [Full Text: https://doi.org/10.1126/science.1073031]
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, 2005. [PubMed: 16195464] [Full Text: https://doi.org/10.1126/science.1114362]
Pignot, V., Hein, A. E., Barske, C., Wiessner, C., Walmsley, A. R., Kaupmann, K., Mayeur, H., Sommer, B., Mir, A. K., Frentzel, S. Characterization of two novel proteins, NgRH1 and NgRH2, structurally and biochemically homologous to the Nogo-66 receptor. J. Neurochem. 85: 717-728, 2003. [PubMed: 12694398] [Full Text: https://doi.org/10.1046/j.1471-4159.2003.01710.x]
Sinibaldi, L., De Luca, A., Bellacchio, E., Conti, E., Pasini, A., Paloscia, C., Spalletta, G., Caltagirone, C., Pizzuti, A., Dallapiccola, B. Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. (Abstract) Hum. Mutat. 24: 534-535, 2004. Note: Full article online. [PubMed: 15532024] [Full Text: https://doi.org/10.1002/humu.9292]
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. [PubMed: 12422217] [Full Text: https://doi.org/10.1038/nature01176]
Wang, K. C., Koprivica, V., Kim, J. A., Sivasankaran, R., Guo, Y., Neve, R. L., He, Z. Oligodendrocyte-myelin glycoprotein in a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417: 941-944, 2002. [PubMed: 12068310] [Full Text: https://doi.org/10.1038/nature00867]
Wong, S. T., Henley, J. R., Kanning, K. C., Huang, K., Bothwell, M., Poo, M. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5: 1302-1308, 2002. [PubMed: 12426574] [Full Text: https://doi.org/10.1038/nn975]
Yu, W., Guo, W., Feng, L. Segregation of Nogo66 receptors into lipid rafts in rat brain and inhibition of Nogo66 signaling by cholesterol depletion. FEBS Lett. 577: 87-92, 2004. [PubMed: 15527766] [Full Text: https://doi.org/10.1016/j.febslet.2004.09.068]
Zheng, B., Atwal, J., Ho, C., Case, L., He, X., Garcia, K. C., Steward, O., Tessier-Lavigne, M. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc. Nat. Acad. Sci. 102: 1205-1210, 2005. [PubMed: 15647357] [Full Text: https://doi.org/10.1073/pnas.0409026102]