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HGNC Approved Gene Symbol: RTN4
Cytogenetic location: 2p16.1 Genomic coordinates (GRCh38) : 2:54,972,189-55,137,831 (from NCBI)
Adult mammalian axon regeneration is generally successful in the peripheral nervous system but poor in the central nervous system. Inhibition results from physical barriers imposed by glial scars, a lack of neurotrophic factors, and growth-inhibitory molecules associated with myelin, the insulating axon sheath. These molecules include NI35, myelin-associated glycoprotein (159460), and Nogo.
Spillmann et al. (1998) identified and purified Nogo, a novel myelin-associated neurite growth inhibitory protein, from bovine spinal cord. They referred to Nogo as NI220 in reference to its neurite growth inhibitory activity and molecular weight.
As part of the Kazusa DNA Research Institute effort to sequence random high molecular weight human brain-derived cDNAs, Nagase et al. (1998) isolated a 4.1-kb cDNA clone (KIAA0886) encoding a protein of molecular mass 135,000 that matched all 6 of the peptide sequences derived from bovine Nogo.
Prinjha et al. (2000) cloned human NOGO cDNAs encoding 3 splice variants. The longest cDNA, designated NOGOA, has an open reading frame of 1,192 amino acids. An intermediate-length splice variant, designated NOGOB, lacks residues 186 to 1004, in the putative extracellular domain. The shortest splice variant, NOGOC, had been described as rat vp20 and foocen-s. NOGOC also lacks residues 186 to 1004 and has a smaller, alternative N-terminal domain. The N-terminal region of NOGO showed no significant homology to any known protein, whereas the C-terminal region was found to share significant homology with neuroendocrine-specific proteins and other members of the reticulon gene family. Prinjha et al. (2000) suggested that NOGO may be a membrane-associated protein consisting of a putative large extracellular domain of 1,024 residues with 7 predicted N-linked glycosylation sites, 2 or 3 transmembrane domains, and a short C-terminal region of 43 residues. Prinjha et al. (2000) developed a soluble version of NOGOA with a relative molecular mass of 220 kD and found it to be a dose-dependent inhibitor of nerve growth.
GrandPre et al. (2000) independently identified NOGO as a member of the reticulon family and designated it reticulon-4A. NOGO is expressed by oligodendrocytes but not by Schwann cells, and associates primarily with the endoplasmic reticulum (ER). A 66-residue luminal/extracellular domain inhibits axonal extension and collapses dorsal root ganglion growth cones. In contrast to NOGO, neither reticulon-1 (600865) nor reticulon-3 (604249) are expressed by oligodendrocytes, and the luminal/extracellular domains from reticulon-1, -2 (603183), and -3 do not inhibit axonal regeneration. GrandPre et al. (2000) suggested that their data provided a molecular basis to assess the contribution of NOGO to the failure of axonal regeneration in the adult central nervous system.
Chen et al. (2000) cloned the rat Nogo cDNA and found 3 isoforms within that species. Antibodies against rat NOGOA were found to stain central nervous system myelin and oligodendrocytes and allow dorsal root ganglion neurites to grow on central nervous system myelin and into optic nerve explants. Chen et al. (2000) concluded that NOGOA is a potent inhibitor of neurite growth and an IN-1 antigen produced by oligodendrocytes, and suggested that their data may allow the generation of new reagents to enhance central nervous system regeneration and plasticity.
The IN-1 antibody recognizes NI35 and NI250-NOGO and allows moderate degrees of axonal regeneration and functional recovery after spinal cord injury. NOGOB, with a relative mass of 37 kD, may correspond to NI35 and explain the antigenic relatedness of the NI35 and NI250 axon outgrowth-inhibiting activity. GrandPre et al. (2000) generated an antiserum directed against the C-terminal luminal/extracellular domain of NOGO. The antibody detected a low level of surface expression, and a Myc epitope at the N or C terminus of expressed NOGO was not detected unless the cells were permeabilized. These data supported a topographic model wherein the N and C termini of the NOGO protein reside in the cytoplasm and 66 residues of the protein protrude on the luminal or extracellular side of the ER or plasma membrane, respectively. Northern blot analysis of NOGO expression using a probe derived from the 5-prime NOGOA/B-specific region detected a single band of 4.1 kb in rat optic nerve but not in sciatic nerve samples, consistent with NOGO functioning as a central nervous system myelin-specific axon outgrowth inhibitor. Northern blot analysis with a probe derived from the 3-prime common region showed that the optic nerve expresses high levels of NOGOA mRNA and much lower levels of NOGOB and NOGOC. Within the reticulon family, optic nerve expression appears to be selective for NOGO with no detectable expression of reticulon-1 or reticulon-3. Reticulon-2 was not examined.
NOGO 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 has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the ER 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 (NGR; 605566) and other glycosylphosphatidylinositol-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 injury.
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 central nervous system 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 central nervous system injury.
Axonal regeneration in the adult central nervous system (CNS) is limited by 2 proteins in myelin, NOGO and myelin-associated glycoprotein (MAG; 159460). The receptor for Nogo (NgR) had been identified as an axonal glycosylphosphatidylinositol (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.
Using a proteomic screen for proteins enriched in caveolin-1 (601047)-containing, cholesterol-rich, buoyant membrane microdomains (CEM/LR), Acevedo et al. (2004) found that NOGOB is enriched in intact blood vessels, smooth muscle cells, and endothelial cells, with its N terminus oriented extracellularly. In vitro, NOGOB promoted vascular cell adhesion and endothelial cell migration, but inhibited the migration of vascular smooth muscle cells, all of which are processes necessary for vascular remodeling. Vascular injury in Nogoa/b-deficient mice resulted in exaggerated neointimal proliferation and, in some cases, vascular occlusion; adenoviral-mediated Nogob gene transfer rescued the abnormal vascular expansion in the knockout mice. Acevedo et al. (2004) concluded that NOGOB is a regulator of vascular homeostasis and remodeling.
Jokic et al. (2005) found that increased levels of NOGOA and NOGOB in muscle biopsies from 15 patients with amyotrophic lateral sclerosis (ALS; 105400) correlated with clinical disability and with the degree of muscle fiber atrophy. NOGOA was detected selectively in atrophic slow-twitch type I fibers. Jokic et al. (2005) suggested that muscle NOGO expression could be a marker for ALS disease severity.
Miao et al. (2006) found that the N-terminal domain of NOGOB induced chemotaxis in human umbilical vein endothelial cells (HUVECs). By screening a heart cDNAs expression library for genes that supported chemotaxis following transfection in COS or CHO cells, they identified NOGOB receptor (NGBR; 610463). NOGOB and NGBR colocalized during angiogenesis induced by VEGF (192240) and wound healing in vivo. NOGOB and NGBR mediated chemotaxis in HUVECs and induced tube formation in 3-dimensional cultures.
Using an in vitro system to identify Xenopus membrane proteins involved in ER network formation, followed by localization, overexpression, and deletion experiments in mammalian and yeast cells, Voeltz et al. (2006) identified the reticulons, particularly Rtn4a/NogoA, and the reticulon-interacting protein DP1/Yop1 (REEP5; 125265) as the major components shaping the tubular ER.
Pradat et al. (2007) found muscle NOGOA expression in 17 of 33 patients with spinal lower motor neuron syndrome observed for 12 months. NOGOA expression correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was detected as early as 3 months after symptom onset in patients who later developed typical ALS. Tagerud et al. (2007) and Askanas et al. (2007) both commented that studies have demonstrated that NOGOA expression is increased in denervated muscles in mouse models and in other human neuropathies and myopathies. Both groups suggested that it may be premature to consider NOGOA muscle expression as a specific biomarker for ALS, as suggested by Pradat et al. (2007).
Using expression cloning, Atwal et al. (2008) found that paired immunoglobulin-like receptor B (PIRB; 604820), which had been implicated in nervous system plasticity, is a high-affinity receptor for NOGO, MAG (159460), and OMGP (164345). Interfering with PIRB activity, either with antibodies or genetically, partially rescued neurite inhibition by NOGO66, MAG, OMGP, and myelin in cultured neurons. Blocking both PIRB and NGR activities led to near-complete release from myelin inhibition. Atwal et al. (2008) concluded that their results implicated PIRB in mediating regeneration block, identified PIRB as a potential target for axon regeneration therapies, and provided an explanation for the similar enhancements of visual system plasticity in PIRB and NGR knockout mice.
Zheng et al. (2003) determined that the mouse Rtn4 gene contains 10 exons and spans more than 50 kb. The first 4 exons are alternatively spliced to generate Nogo transcripts A, B, and C, whereas the last 6 exons are common to all 3 variants.
By radiation hybrid analysis, Nagase et al. (1998) mapped the NOGO gene to chromosome 2. By the same method, Yang et al. (2000) localized the gene to 2p14-p13.
Kim et al. (2003) disrupted expression of Nogoa and Nogob, but not Nogoc, in mice. Brain size and gross anatomy were normal in adult homozygous mutants. Nogoa/Nogob-null mice showed no developmental abnormalities, and neurologic exam and locomotor analysis found no deficits. Unlike wildtype myelin, myelin lacking Nogoa and Nogob did not inhibit axonal outgrowth of dorsal root ganglion cells in culture. Axonal regeneration following hemisection of the descending corticospinal tract (CST) was prominent in a majority of Nogoa/Nogob-null mice, and their locomotor recovery was enhanced over control animals. Simonen et al. (2003) found similar results following disruption of Nogoa expression in mice.
Zheng et al. (2003) reported that myelin from Nogoa/Nogob-null mice showed reduced inhibition of neurite outgrowth, but Nogoa/Nogob deletion had no effect on CST axon regeneration following hemisection. There was no difference between mutant and wildtype animals in functional recovery following injury. Zheng et al. (2003) found that disruption of 3-prime exons common to Nogoa, Nogob, and Nogoc resulted in a high degree of embryonic lethality. Nogoa/Nogob/Nogoc-null mice derived from a surviving male also lacked enhanced axonal regeneration.
Using an experimental autoimmune encephalomyelitis (EAE) mouse model for multiple sclerosis (MS; 126200), Karnezis et al. (2004) showed that both active and passive immunization against Nogoa suppressed clinical signs, demyelination, and axonal damage associated with the disease. The mice that were vaccinated or infused with a Nogoa antibody had delayed disease onset, a decrease in pathologic inflammatory lesions, and a shift in cytokine balance. Karnezis et al. (2004) concluded that specific blockade of NOGOA may aid in maintaining neuronal integrity in the CNS in certain neurodegenerative diseases.
Liebscher et al. (2005) found that intrathecal administration of anti-Nogaa monoclonal IgG antibodies to rats with spinal cord injuries resulted in improvement in motor behavior and enhanced regeneration of corticospinal axons compared to control animals. In addition, functional MRI studies indicated enhanced somatosensory cortical responses to stimulation of the hind paw in animals that received antibodies. Liebscher et al. (2005) hypothesized that Nogoa antibodies enhanced the lesion-induced growth response of axotomized neurons in the injured CNS and induced growth in noninjured neurons.
In mice with EAE, Yang et al. (2010) found that inhibition of Nogoa using small interfering RNA (siRNA) resulted in suppression of Nogoa expression and functional neurologic recovery. Myelin-specific T-cell proliferation and cytokine production were unchanged, and the response was determined to result from increased axonal repair, as demonstrated by enhanced GAP43 (162060)-positive axons in the lesions. Of note, mice given the treatment at the time of disease onset showed a better response than those given treatment at the time of disease induction, indicating that a compromised blood-brain barrier was necessary for the siRNA to gain access to the central nervous system. The findings indicated that inhibition of NogoA can promote neuronal repair and functional recovery in a mouse model of MS.
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