Affinage

RTN4R

Reticulon-4 receptor · UniProt Q9BZR6

Length
473 aa
Mass
50.7 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RTN4R (NgR1) is a GPI-anchored neuronal leucine-rich-repeat receptor that integrates diverse extracellular growth-inhibitory cues to restrict axon regeneration and shape synaptic plasticity in the CNS (PMID:22406547, PMID:18337405, PMID:26586827). It binds the glycosaminoglycan moiety of chondroitin sulfate proteoglycans, and combined loss of NgR1 and NgR3 reproduces the enhanced optic-nerve regeneration of triple Nogo-receptor mutants, establishing it as a functional CSPG receptor (PMID:22406547). NgR1 is specifically required for acute growth-cone collapse evoked by soluble myelin inhibitors (Nogo-66, MAG, OMgp) but is dispensable for chronic substrate-bound neurite inhibition, dissociating these two inhibitory activities (PMID:17611264); consistent with this, NgR1 and NgR2 contribute only modestly to chronic MAG-mediated inhibition of sensory neurons, where additional receptors operate (PMID:19367338). Lacking a transmembrane domain, NgR1 transduces signals through co-receptor complexes: AMIGO3 can substitute for LINGO-1 in an NgR1–p75/TROY complex to activate RhoA after CNS injury (PMID:23613963), and Nogo-A recruits CRMP2 into an NgR1/PlexinA2 ternary complex that drives cellular contraction and constrains corticospinal sprouting in vivo (PMID:30804090). Downstream, NgR signaling activates a RhoA/ROCK/LIM-kinase/cofilin axis producing actin depolymerization and growth-cone collapse, alongside a Ca2+-dependent EGFR-phosphorylation arm (PMID:16613894); loss of NgR1 disinhibits neurotrophin- and FGF2-driven neurite outgrowth on myelin (PMID:15737741). The ectodomain is shed by TACE/ADAM17, generating a soluble decoy that competitively antagonizes ligand binding and suppresses RhoA activation (PMID:16849393), a property exploited therapeutically by NgR1(310)-Fc decoys that promote axon regeneration and neuroprotection after optic-nerve and spinal-cord injury (PMID:25655801, PMID:24964223). Beyond axon growth, NgR1 directly binds FGF1/FGF2 at hippocampal synapses where its loss enhances LTP and alters dendritic spine morphology (PMID:18337405), it bidirectionally regulates spine density, complexity, and learning behavior (PMID:26838771), and it operates outside the nervous system as a cell-surface entry receptor for mammalian reovirus (PMID:24922571) and as an inhibitory immune checkpoint that destabilizes the NK-cell immunological synapse through F-actin regulation (PMID:36624164). Rare RTN4R missense variants from schizophrenia patients impair growth-cone formation, linking receptor structure to cytoskeletal control (PMID:28892071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Low

    Establishing that the NgR gene family is conserved across vertebrates provided the evolutionary framework for studying RTN4R orthologs and their function.

    Evidence Comparative genomics, synteny and phylogenetic analysis, and in situ hybridization in fish

    PMID:12949137

    Open questions at the time
    • Sequence/expression conservation only, no functional assay
    • Does not address whether ortholog function is conserved
  2. 2004 Low

    The first link between RTN4R and human disease asked whether LRR-domain variants contribute to schizophrenia, identifying candidate missense mutations absent from controls.

    Evidence DHPLC mutation screening of patients and molecular modeling of the LRR domain

    PMID:15532024

    Open questions at the time
    • Computational prediction only, no functional assay of mutant protein
    • No demonstration of causality or mechanism
  3. 2005 Medium

    Direct loss-of-function tested whether NgR is genuinely required for myelin inhibition, showing siRNA knockdown disinhibits neurotrophin-induced outgrowth on CNS myelin.

    Evidence siRNA knockdown in DRG neurons with neurite outgrowth quantification on myelin substrate

    PMID:15737741

    Open questions at the time
    • Single method, single lab
    • Did not define downstream signaling
  4. 2006 Medium

    These studies mapped the intracellular signaling logic of NgR, placing it upstream of a RhoA/ROCK/LIM-kinase/cofilin actin-depolymerization pathway and a Ca2+/EGFR arm, and showed that TACE-mediated ectodomain shedding generates a competitive decoy.

    Evidence Schwann cell conditioned medium and exogenous TACE on RGC/DRG cultures, RhoA and EGFR phosphorylation assays, p75NTR siRNA, NgRECD shedding Western blots

    PMID:16613894 PMID:16849393

    Open questions at the time
    • Pathway placement inferred from single lab
    • Stoichiometry of receptor complex not resolved
  5. 2007 High

    Genetic and knockdown dissection resolved a key ambiguity by showing NgR1 is required for acute growth-cone collapse by soluble inhibitors but dispensable for chronic substrate-bound inhibition.

    Evidence Germline NgR1 knockout plus shRNAi across multiple neuron types in two assay paradigms

    PMID:17611264

    Open questions at the time
    • Identity of receptor mediating chronic inhibition unresolved
    • Mechanism of acute-versus-chronic dissociation not defined
  6. 2008 High

    Discovery that NgR1 directly binds FGF1/FGF2 and localizes with FGFR1 at synapses extended its role from axon inhibition to activity-dependent synaptic plasticity and spine morphology.

    Evidence Direct binding assays, synaptosomal fractionation, hippocampal slice LTP/LTD with FGFR inhibitor, NgR1 knockout mice

    PMID:18337405

    Open questions at the time
    • Co-receptor requirement for FGF antagonism not defined
    • Molecular nature of NgR1-FGFR1 functional interaction unresolved
  7. 2009 High

    Quantitative genetic and species-comparison studies refined the receptor's contribution, showing NgR1/NgR2 only modestly mediate chronic MAG inhibition and that species differences in regeneration arise downstream of receptor binding.

    Evidence ngr1/ngr2 double-knockout DRG neurons with ganglioside removal and MAG domain mutants; cross-species Nogo66 binding and cofilin phosphorylation assays with PI-PLC

    PMID:19367338 PMID:20007473

    Open questions at the time
    • Additional MAG receptors not identified
    • Basis for differential downstream signaling across species unknown
  8. 2013 Medium

    Identification of AMIGO3 as an alternative co-receptor explained how the NgR1-p75/TROY complex transduces RhoA activation acutely after injury when LINGO-1 is unavailable.

    Evidence Co-IP in non-neuronal cells and brain lysates, RhoA assay, AMIGO3 siRNA in DRG/retinal cultures, in vivo lesion models

    PMID:23613963

    Open questions at the time
    • Single lab, Co-IP without reciprocal structural validation
    • Selection between LINGO-1 and AMIGO3 not mechanistically defined
  9. 2014 High

    These studies expanded NgR1's biology beyond neurite inhibition, identifying it as a reovirus entry receptor and as a co-receptor mediating myocilin-stimulated oligodendrocyte differentiation.

    Evidence Gain-of-function expression, soluble decoy, null neurons and differential virion/ISVP binding for reovirus; myocilin-null mice, OPC cultures and Lingo-1 Co-IP

    PMID:24741044 PMID:24922571

    Open questions at the time
    • Reovirus capsid component engaging NgR1 not defined at residue level
    • Myocilin role as direct ligand inferred from Co-IP
  10. 2015 High

    Sensitive tracing and decoy-protein interventions established NgR1 as a restraint on corticospinal/raphespinal/RGC regeneration and validated NgR1(310)-Fc as a regeneration- and neuroprotection-promoting therapeutic.

    Evidence crym-GFP CST labeling in ngr1-/- mice after hemisection; intravitreal and intrathecal NgR1(310)-Fc with axon tracing, neuroprotection and pharmacokinetics

    PMID:24964223 PMID:25655801 PMID:26586827

    Open questions at the time
    • Magnitude of regeneration remains modest
    • Decoy target selectivity among NgR ligands not fully resolved
  11. 2016 Medium

    Bidirectional genetic manipulation showed NgR1 negatively regulates dendritic spine density and complexity and influences learning, memory, and cocaine-induced plasticity.

    Evidence NgR1 knockout and overexpression mice with behavioral paradigms, MRI/DTI, and Golgi spine morphometry

    PMID:26838771

    Open questions at the time
    • Region-specific molecular mediators of spine regulation unclear
    • Link between spine phenotype and behavior correlative
  12. 2017 Medium

    Functional testing of a rare schizophrenia-associated R292H variant connected RTN4R structural variation to impaired growth-cone formation.

    Evidence Exon sequencing plus in vitro growth-cone formation assay with mutant

    PMID:28892071

    Open questions at the time
    • Single lab functional assay
    • Disease causality not established
  13. 2019 High

    Biochemical and genetic epistasis identified the NgR1/PlexinA2/CRMP2 ternary complex as the transducer linking Nogo-A to cytoskeletal contraction and corticospinal sprouting restriction in vivo.

    Evidence NgR1 Co-IP plus mass spectrometry, cell contraction assay, double-heterozygous epistasis mice with pyramidotomy and behavioral recovery

    PMID:30804090

    Open questions at the time
    • How CRMP2 couples the complex to RhoA/cytoskeleton not fully resolved
    • Whether the complex operates for ligands other than Nogo-A unclear
  14. 2023 High

    Beyond the nervous system, NgR1 was defined as an inhibitory immune checkpoint that destabilizes the NK-cell immunological synapse, with deficiency or blockade improving tumor control.

    Evidence NgR1 knockout/blockade NK cells, live imaging of immunological synapse and F-actin dynamics, cytotoxicity and in vivo tumor assays

    PMID:36624164

    Open questions at the time
    • Ligand engaging NgR1 on NK cells not identified
    • Signaling pathway downstream of NgR1 in NK cells undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NgR1 selects among its many ligands and co-receptors (CSPGs, Nogo-66, MAG, OMgp, FGFs, reovirus) to produce context-specific outputs, and what receptors mediate chronic myelin inhibition independently of NgR1.
  • No structural model of full ligand/co-receptor selectivity
  • Identity of NgR1-independent chronic-inhibition receptors unknown
  • Mechanism integrating synaptic, immune, and viral roles unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 1
Partners
AMIGO3CRMP2FGFR1JAM-ALINGO-1P75NTRPLXNA2TROY
Complex memberships
NgR1/PlexinA2/CRMP2NgR1/p75(NTR)/LINGO-1 or AMIGO3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 NgR1 (RTN4R) binds with high affinity to the glycosaminoglycan moiety of chondroitin sulfate proteoglycans (CSPGs) and participates in CSPG-mediated inhibition of cultured neurons. In vivo, combined loss of NgR1 and NgR3 (but not NgR1 and NgR2) mimics the triple Nogo receptor mutant phenotype of enhanced axonal regeneration after optic nerve crush, identifying NgR1 as a functional CSPG receptor. High-affinity binding assays, primary neuron inhibition assays, genetic knockout (single, double, triple mutant mice), retro-orbital optic nerve crush with axon regeneration quantification Nature neuroscience High 22406547
2008 NgR1 directly binds FGF1 and FGF2 with high affinity (but not NgR2 or NgR3). NgR1 is enriched in synaptosomal fractions of hippocampus and co-localizes with FGFR1 at synapses. Loss of NgR1 leads to FGF2-dependent enhancement of LTP and attenuation of LTD at Schaffer collateral-CA1 synapses; FGFR kinase activity is required for FGF2-elicited LTP enhancement in NgR1 mutants. NgR1 loss also alters dendritic spine morphology along apical dendrites of hippocampal CA1 neurons. Direct binding assays (high-affinity), synaptosomal fractionation, confocal co-localization, NgR1 knockout mice, hippocampal slice electrophysiology (LTP/LTD), FGFR kinase inhibitor pharmacology, in vitro axonal branching assay The Journal of neuroscience High 18337405
2007 Neuronal NgR1 is required for acute growth cone collapse induced by soluble MAG-Fc, OMgp-Fc, and Nogo-66, but is NOT required for chronic substrate-bound inhibition of neurite outgrowth by MAG or OMgp. Thus the growth cone-collapsing and substrate growth-inhibitory activities of myelin inhibitors can be dissociated, and chronic axon growth inhibition by myelin operates through NgR1-independent mechanisms. Germline NgR1 knockout, shRNAi knockdown in primary cerebellar/sensory/cortical neurons, two-paradigm assay (chronic substrate inhibition vs. acute soluble collapse) The Journal of neuroscience High 17611264
2014 NgR1 functions as a cell-surface receptor for mammalian reovirus on neurons. Expression of NgR1 in non-susceptible cells confers reovirus binding and infection. Soluble NgR1 neutralizes reovirus infectivity. Blocking NgR1 on transfected cells or primary cortical neurons abrogates reovirus infection. Reovirus virions bind both soluble JAM-A and NgR1, whereas infectious subviral particles (ISVPs) bind only JAM-A, indicating distinct capsid components engage these two receptors. Gain-of-function expression in non-susceptible cells, soluble decoy neutralization, antibody blocking, NgR1 null primary cortical neurons, binding assays with virions vs. ISVPs Cell host & microbe High 24922571
2013 AMIGO3 physically interacts with NgR1-p75/TROY in non-neuronal cells and in brain lysates, mediating RhoA activation in response to CNS myelin. AMIGO3 knockdown in adult primary DRG and retinal cultures promotes disinhibited neurite growth. AMIGO3 substitutes for LINGO-1 in the NgR1-p75/TROY inhibitory signalling complex acutely after CNS injury. Co-immunoprecipitation (non-neuronal cells and brain lysates), RhoA activation assay, siRNA knockdown in primary DRG and retinal cultures, in vivo lesion models (dorsal column, optic nerve crush) PloS one Medium 23613963
2006 TACE (ADAM17) induces shedding of the NgR extracellular domain (NgRECD) from DRG neurons. Shed NgRECD acts as a competitive antagonist blocking inhibitory ligand binding to full-length NgR. TACE-induced NgR cleavage also reduces RhoA activation and EGFR phosphorylation downstream of the NgR/p75NTR complex, disinhibiting FGF2-stimulated neurite outgrowth in the presence of CNS myelin. TACE addition to DRG neuron cultures, Western blot for NgRECD shedding, RhoA activation assay, EGFR phosphorylation assay, neurite outgrowth quantification FASEB journal Medium 16849393
2006 NgR signals through a Ca2+-dependent pathway that activates EGFR phosphorylation, and through a Rho-A/ROCK/LIM-kinase/cofilin phosphorylation pathway leading to actin depolymerization and growth cone collapse. Schwann cell-derived factors (including TACE) cleave the NgR ectodomain; the shed NgRECD competitively antagonizes inhibitory ligand/NgR binding, blocking p75NTR/NgR clustering, reducing EGFR phosphorylation and suppressing RhoA activation. siRNA knockdown of p75NTR also inactivates RhoA and disinhibits neurotrophic factor-stimulated RGC neurite outgrowth. Schwann cell conditioned medium on RGC cultures, exogenous TACE application, siRNA knockdown of p75NTR, EGFR phosphorylation assay, RhoA activation assay, optic nerve regeneration in vivo Brain Medium 16613894
2005 siRNA-mediated knockdown of NgR (100% protein reduction) in DRG neurons disinhibits neurotrophin-induced neurite outgrowth on CNS myelin, with a 50% increase in outgrowth at 48 h and a 3.5-fold increase in βIII-tubulin at 3 days, placing NgR as a required component of the CNS myelin inhibitory signaling cascade in DRG neurons. siRNA knockdown (RNAi) in DRG neurons, neurite outgrowth quantification on CNS myelin substrate, Western blot protein quantification Molecular and cellular neurosciences Medium 15737741
2019 Nogo-A exposure to neurons recruits CRMP2 into an NgR1 immunoprecipitate in a PlexinA2-dependent manner, forming a NgR1/PlexinA2/CRMP2 ternary complex. Non-neuronal cells expressing both NgR1 and PlexinA2 (but not either alone) contract upon Nogo-A exposure. Double-heterozygous NgR1+/-/PlexinA2+/- neurons are rescued from Nogo-A inhibition (epistasis), and double-heterozygous mice show greater post-injury corticospinal sprouting and neurological recovery after pyramidotomy. NgR1 co-immunoprecipitation + mass spectrometry, non-neuronal cell contraction assay, genetic epistasis (double-heterozygous mice), pyramidotomy + anterograde tracing, behavioral recovery assessment The Journal of neuroscience High 30804090
2015 NgR1 is required to restrict corticospinal tract (CST) axon regeneration after dorsal hemisection. Using comprehensive crym-GFP CST labeling (~10-fold more efficient than BDA), ngr1-/- mice showed significant CST axon regeneration (average 2.68% of labeled axons extending >100 μm past lesion) that was undetectable with traditional BDA tracing, whereas ngr1+/+ mice showed no significant regeneration. crym-GFP transgenic reporter mice for comprehensive CST labeling, ngr1 genetic knockout, dorsal hemisection spinal cord injury, quantitative axon counting The Journal of neuroscience High 26586827
2004 Two missense mutations in RTN4R (R119W, R196H) identified in schizophrenic patients alter residues in the leucine-rich repeat domain; molecular modeling predicts structural alterations of the native GPI-anchored protein. Both mutations were absent in 300 controls. DHPLC mutation screening, molecular modeling of LRR domain Human mutation Low 15532024
2017 A rare RTN4R missense variant R292H, identified in schizophrenia patients, impairs growth cone formation in vitro functional assays, linking NgR1 structure to cytoskeletal regulation of growth cones. Exon sequencing, in vitro growth cone formation assay with R292H mutant Translational psychiatry Medium 28892071
2009 Zebrafish Nogo66 (ZF-Nogo66) is growth-permissive rather than inhibitory for both zebrafish and mouse neurons, in contrast to rat Nogo66. Both ZF- and rat-Nogo66 bind NgR (GPI-anchored receptor) in fish and mouse neurons. Rat-Nogo66 elicits phosphorylation of the downstream effector cofilin, whereas ZF-Nogo66 does not, demonstrating that differential downstream signaling (rather than receptor binding) accounts for the species difference in regenerative capacity. Outgrowth assay, growth cone collapse assay, contact assay across species, PI-PLC treatment to identify GPI-anchored receptor involvement, cofilin phosphorylation assay The Journal of neuroscience Medium 20007473
2014 Myocilin, secreted by optic nerve astrocytes, stimulates oligodendrocyte differentiation through the NgR1/Lingo-1 receptor complex. Myocilin physically interacts (co-immunoprecipitation) with Lingo-1 and may act as a Lingo-1 ligand; myocilin-induced elongation of oligodendrocyte processes is mediated by activation of FYN and suppression of RhoA GTPase. Myocilin-null mouse analysis, primary oligodendrocyte precursor culture assays, co-immunoprecipitation (myocilin-Lingo-1), FYN/RhoA activity assays The Journal of neuroscience Medium 24741044
2023 NgR1 functions as an inhibitory immune checkpoint in NK cells by destabilizing the immunological synapse (IS). NgR1 deficiency or blockade improves tumor control by enhancing NK cell-to-target contact stability and regulating F-actin dynamics during IS formation. NgR1 knockout NK cells, NgR1 blockade, live imaging of immunological synapse formation, F-actin dynamics assay, NK cell cytotoxicity assays, tumor control in vivo Nature immunology High 36624164
2013 In aged cognitively impaired rats, hippocampal NgR1 co-receptor proteins LINGO-1, p75, and TROY are significantly elevated and co-localize with NgR1 in hippocampal neurons, suggesting an assembled signaling complex. Downstream RhoA is also elevated. Expression levels of all components correlate significantly with Morris water maze performance, placing the NgR1/LINGO-1 or NgR1/p75/TROY complex as a pathway suppressing synaptic plasticity in cognitive decline. Protein expression quantification (Western blot), immunohistochemical co-localization, Morris water maze behavioral classification, correlation analysis The European journal of neuroscience Low 23438185
2015 NgR1 is a negative regulator of dendritic spine density (mature spine density reduced by NgR1 overexpression) and dendritic complexity in a brain region-specific manner. NgR1 overexpression impairs sequential spatial learning; NgR1 loss impairs locomotor behavior and recognition memory. NgR1 also modulates cocaine-induced synaptic spine plasticity and behavioral sensitization. NgR1 knockout and transgenic overexpression mice, serial behavioral paradigms (locomotor, recognition memory, spatial learning), ex vivo MRI/DTI, dendritic spine morphometry (Golgi staining), cocaine sensitization protocol Cerebral cortex Medium 26838771
2018 Osmotin reduces NgR1 expression and inhibits formation of the Nogo-A/NgR1 ligand-receptor complex via AdipoR1, resulting in enhanced neurite outgrowth. These effects disappeared with AdipoR1 interference, placing AdipoR1 upstream of NgR1 in osmotin's mechanism of action. AdipoR1 siRNA knockdown, Western blot for NgR1 and Nogo-A, co-immunoprecipitation (Nogo-A/NgR1 complex), neurite outgrowth assay in Alzheimer's disease mouse neurons Molecular neurobiology Medium 29335844
2015 Intravitreal delivery of human NgR1(310)-Fc decoy protein promotes retinal ganglion cell (RGC) axonal regeneration after optic nerve crush and protects large-diameter RGCs from elevated IOP-induced death in a microbead glaucoma model, without reducing IOP. Pharmacokinetic analysis showed a terminal half-life of ~24 hours in vitreous after bolus administration. Intravitreal injection, cholera toxin β anterograde axon labeling, retrograde Fluoro-Gold RGC counting, microbead IOP model, pharmacokinetic ELISA Investigative ophthalmology & visual science Medium 25655801
2011 NgR is expressed on oligodendrocyte progenitor cells (OPCs) but not on mature oligodendrocytes. Blocking NgR on OPCs with antibody under proliferating conditions prolongs processes via PI3K/Akt signaling, but under differentiating conditions, NgR blockade inhibits OPC differentiation via ERK1/2 signaling—demonstrating a pro-differentiation function of NgR in OPCs that is distinct from its inhibitory role in neurons. Immunostaining and Western blot for NgR on NPCs/OPCs/oligodendrocytes, anti-NgR antibody blockade, proliferation and differentiation assays, PI3K/Akt and ERK1/2 pathway inhibitor pharmacology Brain research Medium 22227458
2015 NgR1 decoy protein (NgR1(310)-Fc) delivered by lumbar intrathecal bolus distributes throughout the neuraxis (half-life ~2 days in rat, ~5 days in nonhuman primate) and promotes locomotor recovery and growth of raphespinal axons into lumbar spinal cord after contusion injury, with intermittent dosing as effective as continuous infusion. Lumbar intrathecal bolus delivery, pharmacokinetic tissue sampling, anterograde raphespinal axon tracing, open field and grid walking behavioral assays in rat contusion SCI Journal of neurotrauma Medium 24964223
2015 NgR1 decoy protein (NgR1(310)-Fc) administered intravitreally promotes RGC axon regeneration after optic nerve crush (increased RGCs with regenerating axons) and protects large-diameter RGCs in a microbead glaucoma model, demonstrating a neuroprotective role for NgR1 blockade independent of IOP. Intravitreal injection, optic nerve crush, cholera toxin β anterograde labeling, retrograde Fluoro-Gold tracing, microbead IOP model Investigative ophthalmology & visual science Medium 25655801
2009 NgR1 and NgR2 make only a modest combined contribution to MAG-mediated inhibition of sensory DRG neuron outgrowth; disrupting both NgR proteins results in only partial attenuation, and eliminating ganglioside binding further reduces but does not abolish inhibition. Thus NgR1 (and NgR2) are NOT the sole or primary mediators of chronic MAG inhibition in sensory neurons, and additional unidentified receptors exist. The Ig-like domains 4 and 5 of MAG are necessary and sufficient for growth arrest, independent of sialic acid binding. ngr1, ngr2, ngr1/ngr2 double-knockout DRG neurons, neuraminidase (VCN) treatment to remove gangliosides, MAG domain deletion mutants, neurite outgrowth assay PloS one High 19367338
2015 NgR1 reduction in the perforant path (via AAV-shRNA) rescues cognitive and synaptic deficits in APP/PS1 mice, decreases Aβ production in the perforant path, and reduces amyloid plaques in the hippocampus. NgR1 overexpression or knockdown in N2a/HEK293-APPswe cells shows a positive correlation with total APP protein and both α- and β-secretase cleavage products. NgR1 may inhibit APP degradation through the lysosomal pathway via Rho/ROCK signaling. AAV-shRNA knockdown in perforant path, APP/PS1 transgenic mice, behavioral assays, LTP measurement, ELISA for Aβ and APP metabolites, AAV overexpression and shRNA in cell lines, lysosomal pathway inhibitors Alzheimer's research & therapy Medium 32331528
2015 Nogo-A/NgR signaling in microglia inhibits cell adhesion and migration to fibrillar Aβ1-42, an effect mediated by NgR and Rho GTPases regulating cytoskeletal arrangement. Blocking NgR with NEP1-40 in APP/PS1 mice enhances microglial recruitment toward Aβ deposits and upregulates CD36 expression. Microglial adhesion and migration (transwell) assays with Nogo-66 and NEP1-40, APP/PS1 mouse intracerebroventricular NEP1-40 delivery, immunohistochemistry for microglial recruitment and CD36 Journal of neuroinflammation Medium 30029608
2015 Nogo-P4 (a 25-amino-acid Nogo-66 core peptide) activates NgR on microglia to induce expression of iNOS, COX-2 and release of IL-1β, TNF-α, NO, and PGE2. This proinflammatory response is reversed by NEP1-40 (NgR antagonist), PI-PLC (GPI-anchor cleavage), or NgR siRNA. The mechanism involves increased phosphorylation of NF-κB and STAT3 downstream of NgR. Primary microglia stimulation with Nogo-P4, NEP1-40 competitive antagonist, PI-PLC treatment, NgR siRNA knockdown, NF-κB and STAT3 phosphorylation assays, cytokine ELISA The Journal of biological chemistry Medium 26472924
2003 Fish (zebrafish and fugu) possess true NgR orthologs with conserved synteny, intron-exon structure, and phylogenetic relationship to human NgR1 (RTN4R), expressed in developing and adult brain. This established the evolutionary conservation of the NgR gene family across vertebrates. Comparative genomics, synteny analysis, intron-exon structure comparison, phylogenetic analysis, in situ hybridization expression analysis Molecular biology and evolution Low 12949137

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nature neuroscience 359 22406547
2014 Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines. Nano letters 239 24422585
2008 The neovasculature homing motif NGR: more than meets the eye. Blood 159 18574027
2008 Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength. The Journal of neuroscience : the official journal of the Society for Neuroscience 149 18337405
2010 Nanoparticles targeted with NGR motif deliver c-myc siRNA and doxorubicin for anticancer therapy. Molecular therapy : the journal of the American Society of Gene Therapy 140 20068551
2014 PEGylated liposomes with NGR ligand and heat-activable cell-penetrating peptide-doxorubicin conjugate for tumor-specific therapy. Biomaterials 103 24565519
2012 Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel. Biomaterials 86 23127332
2007 The Nogo-66 receptor NgR1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 17611264
2005 Disinhibition of neurotrophin-induced dorsal root ganglion cell neurite outgrowth on CNS myelin by siRNA-mediated knockdown of NgR, p75NTR and Rho-A. Molecular and cellular neurosciences 83 15737741
2007 Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects. Anti-cancer drugs 78 17893520
2015 Dual-modified liposomes with a two-photon-sensitive cell penetrating peptide and NGR ligand for siRNA targeting delivery. Biomaterials 76 25701034
2010 Critical role of flanking residues in NGR-to-isoDGR transition and CD13/integrin receptor switching. The Journal of biological chemistry 74 20064928
2014 The Nogo receptor NgR1 mediates infection by mammalian reovirus. Cell host & microbe 73 24922571
2006 Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. Brain : a journal of neurology 73 16613894
2006 TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 73 16849393
2009 NGR-modified micelles enhance their interaction with CD13-overexpressing tumor and endothelial cells. Journal of controlled release : official journal of the Controlled Release Society 70 19470394
2018 NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. Oncology 69 29753703
2003 HBO suppresses Nogo-A, Ng-R, or RhoA expression in the cerebral cortex after global ischemia. Biochemical and biophysical research communications 67 12951059
2012 Synthesis and evaluation of 64Cu-labeled monomeric and dimeric NGR peptides for MicroPET imaging of CD13 receptor expression. Molecular pharmaceutics 61 23190134
2004 Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Human mutation 59 15532024
2016 Panax notoginseng saponins provide neuroprotection by regulating NgR1/RhoA/ROCK2 pathway expression, in vitro and in vivo. Journal of ethnopharmacology 54 27288754
2007 Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches. PloS one 51 18043741
2005 Immunogenic and structural properties of the Asn-Gly-Arg (NGR) tumor neovasculature-homing motif. Molecular immunology 46 16337683
2010 The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats. Journal of drug targeting 45 20677914
2008 Immunization with recombinant Nogo-66 receptor (NgR) promotes axonal regeneration and recovery of function after spinal cord injury in rats. Neurobiology of disease 45 18930141
2006 Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat. Experimental neurology 43 16321384
2019 Notoginsenoside R1 (NGR1) Attenuates Chronic Atrophic Gastritis in Rats. Medical science monitor : international medical journal of experimental and clinical research 38 30757999
2018 NGR (Asn-Gly-Arg)-targeted delivery of coagulase to tumor vasculature arrests cancer cell growth. Oncogene 38 29662195
2015 Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1-/- Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 26586827
2025 NGR-Modified CAF-Derived exos Targeting Tumor Vasculature to Induce Ferroptosis and Overcome Chemoresistance in Osteosarcoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 37 39889249
2017 NGR-peptide-drug conjugates with dual targeting properties. PloS one 37 28575020
2015 The Nogo/Nogo Receptor (NgR) Signal Is Involved in Neuroinflammation through the Regulation of Microglial Inflammatory Activation. The Journal of biological chemistry 37 26472924
2012 NGR peptide ligands for targeting CD13/APN identified through peptide array screening resemble fibronectin sequences. ACS combinatorial science 37 23030271
2016 The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice. Journal of neuroinflammation 36 26939570
2015 Intravitreal delivery of human NgR-Fc decoy protein regenerates axons after optic nerve crush and protects ganglion cells in glaucoma models. Investigative ophthalmology & visual science 35 25655801
2013 (99m)Tc-labeled monomeric and dimeric NGR peptides for SPECT imaging of CD13 receptor in tumor-bearing mice. Amino acids 35 23456486
2009 No Nogo66- and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 20007473
2015 A photo-responsive peptide- and asparagine-glycine-arginine (NGR) peptide-mediated liposomal delivery system. Drug delivery 31 25693640
2013 AMIGO3 is an NgR1/p75 co-receptor signalling axon growth inhibition in the acute phase of adult central nervous system injury. PloS one 31 23613963
2013 68Ga-DOTA-NGR as a novel molecular probe for APN-positive tumor imaging using MicroPET. Nuclear medicine and biology 31 24438818
2020 Tanshinone IIA Promotes Axonal Regeneration in Rats with Focal Cerebral Ischemia Through the Inhibition of Nogo-A/NgR1/RhoA/ROCKII/MLC Signaling. Drug design, development and therapy 30 32764877
2018 The adhesion and migration of microglia to β-amyloid (Aβ) is decreased with aging and inhibited by Nogo/NgR pathway. Journal of neuroinflammation 30 30029608
2014 Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion. Journal of neurotrauma 30 24964223
2009 Inhibitory activity of myelin-associated glycoprotein on sensory neurons is largely independent of NgR1 and NgR2 and resides within Ig-Like domains 4 and 5. PloS one 30 19367338
2014 68Ga-labeled cyclic NGR peptide for microPET imaging of CD13 receptor expression. Molecules (Basel, Switzerland) 29 25100253
2006 Expression of Nogo-A and NgR in the developing rat brain after hypoxia-ischemia. Brain research 29 16928363
2003 Identification of Nogo-66 receptor (NgR) and homologous genes in fish. Molecular biology and evolution 29 12949137
2018 The Adiponectin Homolog Osmotin Enhances Neurite Outgrowth and Synaptic Complexity via AdipoR1/NgR1 Signaling in Alzheimer's Disease. Molecular neurobiology 28 29335844
2015 Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery. Journal of drug targeting 28 26176270
2014 Myocilin is involved in NgR1/Lingo-1-mediated oligodendrocyte differentiation and myelination of the optic nerve. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 24741044
2012 NGR-based strategies for targeting delivery of chemotherapeutics to tumor vasculature. Anti-cancer agents in medicinal chemistry 28 22263803
2011 Combined NgR vaccination and neural stem cell transplantation promote functional recovery after spinal cord injury in adult rats. Neuropathology and applied neurobiology 27 20819171
2012 Development of NGR-based anti-cancer agents for targeted therapeutics and imaging. Anti-cancer agents in medicinal chemistry 26 22023047
2012 Alpha tocopherol treatment reduces the expression of Nogo-A and NgR in rat brain after traumatic brain injury. The Journal of surgical research 26 23207171
2013 Oxidation-induced structural changes of ceruloplasmin foster NGR motif deamidation that promotes integrin binding and signaling. The Journal of biological chemistry 25 24366863
2011 Expression and function of myelin-associated proteins and their common receptor NgR on oligodendrocyte progenitor cells. Brain research 25 22227458
2023 NgR1 is an NK cell inhibitory receptor that destabilizes the immunological synapse. Nature immunology 24 36624164
2020 Research Progress of Radiolabeled Asn-Gly-Arg (NGR) Peptides for Imaging and Therapy. Molecular imaging 24 32862776
2016 NgR1: A Tunable Sensor Regulating Memory Formation, Synaptic, and Dendritic Plasticity. Cerebral cortex (New York, N.Y. : 1991) 24 26838771
2009 Patterns of Nogo-A, NgR, and RhoA expression in the brain tissues of rats with focal cerebral infarction. Translational research : the journal of laboratory and clinical medicine 24 19524873
2019 Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA. eLife 23 31361595
2019 SATB2 and NGR1: potential upstream regulatory factors in uterine leiomyomas. Journal of assisted reproduction and genetics 23 31728810
2014 Near-infrared fluorescence imaging of CD13 receptor expression using a novel Cy5.5-labeled dimeric NGR peptide. Amino acids 23 24652439
2014 Yonkenafil: a novel phosphodiesterase type 5 inhibitor induces neuronal network potentiation by a cGMP-dependent Nogo-R axis in acute experimental stroke. Experimental neurology 23 25064698
2005 Expression pattern of NOGO and NgR genes during human development. Gene expression patterns : GEP 23 15749087
2019 Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 30804090
2018 NGR-hTNF and Doxorubicin as Second-Line Treatment of Patients with Small Cell Lung Cancer. The oncologist 22 30076277
2017 A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility. Translational psychiatry 22 28892071
2016 Multi-targeting NGR-modified liposomes recognizing glioma tumor cells and vasculogenic mimicry for improving anti-glioma therapy. Oncotarget 22 27283987
2023 Non-covalent strategies to functionalize polymeric nanoparticles with NGR peptides for targeting breast cancer. International journal of pharmaceutics 21 36657553
2020 Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) Inhibits Autophagic Activation and Prevents Secondary Neuronal Damage in the Thalamus after Focal Cerebral Infarction in Hypertensive Rats. Neuroscience 21 32068082
2020 Reduction of NgR in perforant path decreases amyloid-β peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice. Alzheimer's research & therapy 21 32331528
2020 Fasudil reduces β-amyloid levels and neuronal apoptosis in APP/PS1 transgenic mice via inhibition of the Nogo-A/NgR/RhoA signaling axis. Journal of integrative neuroscience 21 33378839
2019 Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling. International journal of molecular sciences 21 31547231
2019 Electroacupuncture Promoting Axonal Regeneration in Spinal Cord Injury Rats via Suppression of Nogo/NgR and Rho/ROCK Signaling Pathway. Neuropsychiatric disease and treatment 21 31997879
2015 Photo-responsive and NGR-mediated multifunctional nanostructured lipid carrier for tumor-specific therapy. Journal of pharmaceutical sciences 21 25630979
2015 Exercise Training Inhibits the Nogo-A/NgR1/Rho-A Signals in the Cortical Peri-infarct Area in Hypertensive Stroke Rats. American journal of physical medicine & rehabilitation 21 26135366
2013 Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition. The European journal of neuroscience 21 23438185
2013 Expression pattern of Nogo-A, MAG, and NgR in regenerating urodele spinal cord. Developmental dynamics : an official publication of the American Association of Anatomists 20 23592243
2014 Effects of curcumin on hippocampal expression of NgR and axonal regeneration in Aβ-induced cognitive disorder rats. Genetics and molecular research : GMR 19 24737429
2007 DNA vaccine against NgR promotes functional recovery after spinal cord injury in adult rats. Brain research 19 17362886
2016 Systemic and tumor-targeted delivery of siRNA by cyclic NGR and isoDGR motif-containing peptides. Biomaterials science 18 26783563
2007 Expression of oligodendrocyte myelin glycoprotein and its receptor NgR after the injury of rat central nervous system. Neuroscience letters 18 17630211
2006 No association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Chinese population. Journal of neural transmission (Vienna, Austria : 1996) 18 16897606
2013 Expression of NgR1-antagonizing proteins decreases with aging and cognitive decline in rat hippocampus. Cellular and molecular neurobiology 17 23525710
2022 Incorporation of NGR1 promotes bone regeneration of injectable HA/nHAp hydrogels by anti-inflammation regulation via a MAPK/ERK signaling pathway. Frontiers in bioengineering and biotechnology 16 36213055
2021 B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF. Scientific reports 16 33536561
2009 NgR RNA interference, combined with zymosan intravitreal injection, enhances optic nerve regeneration. Journal of neurochemistry 16 19575706
2018 Effects of MicroRNA-494 on Astrocyte Proliferation and Synaptic Remodeling in the Spinal Cord of a Rat Model of Chronic Compressive Spinal Cord Injury by Regulating the Nogo/Ngr Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 30036869
2014 Zuo-Gui and You-Gui pills, two traditional Chinese herbal formulas, downregulated the expression of NogoA, NgR, and RhoA in rats with experimental autoimmune encephalomyelitis. Journal of ethnopharmacology 15 25448504
2011 Anti-tumor efficacy and pre-clinical immunogenicity of IFNα2a-NGR. Regulatory toxicology and pharmacology : RTP 15 21338646
2011 Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis. PloS one 15 22096481
2022 Heterodimeric RGD-NGR PET Tracer for the Early Detection of Pancreatic Cancer. Molecular imaging and biology 14 35229260
2017 In vitro and in vivo evaluation of novel NGR-modified liposomes containing brucine. International journal of nanomedicine 14 28860749
2022 Modulation of the Microglial Nogo-A/NgR Signaling Pathway as a Therapeutic Target for Multiple Sclerosis. Cells 13 36497029
2021 Constraint-Induced Movement Therapy Promotes Neural Remodeling and Functional Reorganization by Overcoming Nogo-A/NgR/RhoA/ROCK Signals in Hemiplegic Cerebral Palsy Mice. Neurorehabilitation and neural repair 13 33410385
2021 A comparison of the monomeric [68Ga]NODAGA-NGR and dimeric [68Ga]NOTA-(NGR)2 as aminopeptidase N ligand for positron emission tomography imaging in tumor-bearing mice. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 13 34375678
2016 Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26768609
2014 In vivo NIRF imaging-guided delivery of a novel NGR-VEGI fusion protein for targeting tumor vasculature. Amino acids 13 25182731
2006 NGR enhanced the anti-angiogenic activity of tum-5. Journal of biochemistry 13 16845126

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