Affinage

RGMA

Repulsive guidance molecule A · UniProt Q96B86

Length
450 aa
Mass
49.4 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGMa is a GPI-anchored repulsive guidance molecule that signals through the transmembrane receptor neogenin to control axon guidance, neural tube closure, immune cell trafficking, and BMP pathway modulation across diverse cell types. In neurons, RGMa binding to neogenin activates RhoA/ROCK/PKC to collapse growth cones and inhibits Ras (via FAK dephosphorylation and p120GAP release) and Akt to suppress axon outgrowth; proteolytic processing by Furin/SKI-1 generates N- and C-terminal fragments that engage distinct downstream pathways—C-RGMa signals through LARG/Rho/ROCK while N-RGMa triggers γ-secretase cleavage of neogenin to produce NeICD/LMO4—and simultaneous binding of netrin-1 and RGMa to neogenin assembles a super-complex that silences both repulsive and attractive outputs (PMID:12353034, PMID:17389603, PMID:19458235, PMID:22340500, PMID:26292756, PMID:33740419). RGMa independently functions as a BMP co-receptor that directly binds BMP-2/4, enhances Smad1/5/8 signaling, and expands type II receptor utilization to include ActRIIA, while in astrocytes it promotes reactive gliosis by scaffolding a TGFβ/ALK5/Smad2/3 complex (PMID:15975920, PMID:17472960, PMID:29396549). In the immune system, RGMa on dendritic cells engages neogenin on T cells to activate Rap1 and ICAM-1-mediated adhesion, repels leukocyte migration, and drives macrophage CXCL2 production to recruit neutrophils in neuroinflammatory lesions; antibody blockade of RGMa ameliorates experimental autoimmune encephalomyelitis, peritonitis, and neuromyelitis optica models (PMID:21423182, PMID:21467223, PMID:35167145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Identifying RGMa as a GPI-anchored axon repellent established the founding molecular activity: it selectively collapses temporal retinal growth cones at nanomolar concentrations, explaining topographic map selectivity in the retinotectal system.

    Evidence Recombinant RGMa in growth cone collapse and stripe assays on chick retinal axons

    PMID:12353034

    Open questions at the time
    • Receptor unknown at this point
    • Intracellular signaling mechanism not identified
    • In vivo loss-of-function not yet performed
  2. 2004 High

    Three concurrent advances identified neogenin as the RGMa receptor, demonstrated that neogenin acts as a dependence receptor whose pro-apoptotic cleavage is suppressed by RGMa, showed RGMa is essential for neural tube closure in mice, and established RGMa as a repulsive cue patterning hippocampal lamination—together defining the core receptor-ligand pair and its developmental necessity.

    Evidence Mouse RGMa knockout (neural tube defect), chick neural tube in ovo electroporation (neogenin dependence receptor), entorhino-hippocampal coculture with neutralizing antibody and PI-PLC

    PMID:14749425 PMID:15084667 PMID:15258591

    Open questions at the time
    • Downstream intracellular signaling cascade still unmapped
    • Relationship between repulsive guidance and dependence receptor functions unclear
  3. 2005 High

    Discovery that RGMa directly binds BMP-2/4 and enhances Smad1/5/8 signaling as a BMP co-receptor revealed a second, guidance-independent signaling axis, broadening RGMa from a pure axon repellent to a multifunctional signaling hub.

    Evidence Radiolabeled BMP binding, co-IP with BMP type I receptors, Smad phosphorylation and Id1 reporter assays

    PMID:15975920

    Open questions at the time
    • How BMP co-receptor and neogenin-mediated repulsive functions are segregated in the same cell unclear
    • Type II receptor utilization not yet addressed
  4. 2006 High

    Demonstrating that RGMa inhibits neurite outgrowth through RhoA/ROCK and that anti-RGMa antibody promotes axon regeneration and functional recovery after spinal cord injury established the therapeutic rationale for blocking RGMa in CNS injury.

    Evidence In vitro neurite outgrowth with RhoA pathway inhibitors; in vivo intrathecal anti-RGMa antibody after rat spinal cord hemisection with axon tracing and behavioral testing

    PMID:16585268

    Open questions at the time
    • Full signaling cascade downstream of neogenin not resolved
    • Contribution of other inhibitory cues in vivo not dissected
  5. 2007 High

    Genetic and pharmacological dissection in neogenin-knockout neurons demonstrated that RGMa collapse requires neogenin→RhoA/ROCK/PKC but is independent of BMP signaling, formally separating the two RGMa signaling arms; concurrently, RGMa was shown to expand BMP type II receptor utilization to ActRIIA.

    Evidence DRG neurons from neogenin−/− mice with dominant-negative RhoA/Rac1 and pharmacological inhibitors; siRNA of type II receptors in BMPRII-null cells with radiolabeled BMP binding (Kd determination)

    PMID:17389603 PMID:17472960

    Open questions at the time
    • How neogenin couples to RhoA activation molecularly unknown
    • Whether both pathways operate simultaneously in the same cell untested
  6. 2008 High

    Showing that RGMa–neogenin signaling regulates microtubule organization and apicobasal polarity during neural fold elevation provided the cell-biological mechanism underlying the neural tube closure defect seen in RGMa knockouts.

    Evidence Morpholino knockdown in Xenopus with microtubule immunostaining and neural tube morphology analysis

    PMID:19036958

    Open questions at the time
    • Direct molecular link between neogenin and microtubule regulators not identified
    • Whether the same polarity mechanism operates in mammals not confirmed
  7. 2009 High

    Identification of the FAK/p120GAP/Ras/Akt cascade downstream of neogenin explained how RGMa simultaneously suppresses survival signaling and activates repulsion: RGMa triggers FAK dephosphorylation, releasing p120GAP to inactivate Ras and Akt, both required for growth cone collapse.

    Evidence Co-IP of FAK–p120GAP, Rho GTPase activity assays, p120GAP siRNA, constitutively active Akt rescue in growth cone collapse assay

    PMID:19458235

    Open questions at the time
    • Phosphatase responsible for FAK Tyr-397 dephosphorylation unknown
    • How RhoA and Ras pathways are coordinated downstream of neogenin not resolved
  8. 2011 High

    Three studies simultaneously expanded RGMa biology into the immune system: RGMa on dendritic cells activates Rap1/ICAM-1-mediated T cell adhesion via neogenin, RGMa repels leukocyte migration in a neogenin-dependent manner, and activated microglia upregulate RGMa to inhibit axonal growth—collectively establishing RGMa–neogenin as a neuroimmune signaling axis.

    Evidence DC–T cell co-culture with Rap1 assay and EAE model (anti-RGMa antibody); leukocyte migration assay and peritonitis model in neogenin gene-trap mice; microglia–neuron co-culture with RGMa siRNA and SCI model

    PMID:21423182 PMID:21467223 PMID:21957482

    Open questions at the time
    • Downstream transcriptional programs in T cells not mapped
    • Whether neogenin on microglia also signals back to neurons unknown
  9. 2012 High

    Biochemical mapping of RGMa proteolytic processing by Furin/SKI-1 and autocatalytic cleavage revealed that multiple fragments (N-RGMa, C-RGMa) all bind neogenin's fibronectin-like domains but engage distinct downstream effectors; separately, RGMa was shown to regulate non-neuronal cell migration via its RGD motif and adhesion via its vWF domain in a neogenin-dependent, BMP-independent manner.

    Evidence Mass spectrometry fragment identification, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants; Xenopus animal cap migration/adhesion assays with deletion mutants

    PMID:22215618 PMID:22340500

    Open questions at the time
    • Stoichiometry of fragment signaling in vivo unknown
    • Whether specific fragments dominate in specific tissues not resolved
  10. 2013 High

    Crystal structures of the NEO1–RGMB complex revealed a novel protein fold and a pH-dependent 2:2 receptor–ligand architecture that applies to all RGM family members, providing the first atomic-resolution model for RGMa–neogenin signaling.

    Evidence X-ray crystallography of NEO1–RGMB complex with functional validation of autocatalytic cleavage

    PMID:23744777

    Open questions at the time
    • Structure of RGMa specifically (not RGMB) in complex with NEO1 not determined
    • How conformational changes propagate to the intracellular domain unknown
  11. 2015 High

    Demonstrating that C-RGMa and N-RGMa fragments activate two distinct pathways—C-RGMa via LARG/Rho/ROCK and N-RGMa via γ-secretase/NeICD/LMO4—with each producing different layer-specific targeting errors in the tectum, resolved how a single ligand generates multiple context-dependent outputs through proteolytic diversification.

    Evidence In ovo electroporation of fragment constructs and dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression in chick tectum with anterograde tracing

    PMID:26292756

    Open questions at the time
    • What determines which fragment predominates at a given synapse unknown
    • Whether both pathways can operate simultaneously in the same neuron untested
  12. 2018 High

    Discovery that RGMa scaffolds a TGFβ/ALK5/Smad2/3 complex in astrocytes to drive reactive gliosis after stroke revealed a third major signaling mode—distinct from both neogenin-mediated repulsion and BMP co-receptor function—linking RGMa to scar formation.

    Evidence Co-IP of RGMa–ALK5–Smad2/3 complex, RGMa siRNA blocking TGFβ1-induced Smad2/3 phosphorylation in primary astrocytes, in vivo MCAO model

    PMID:29396549

    Open questions at the time
    • Whether RGMa binds ALK5 directly or through an intermediary unclear
    • Relative contribution of BMP vs. TGFβ arms to glial scar unknown
  13. 2019 High

    Showing that RGMa-induced neogenin glycosylation and intramembrane proteolysis generates a nuclear NeoICD fragment essential for neuroepithelial cell elongation during neurulation provided the mechanistic link between RGMa signaling and the microtubule-dependent cell shape changes underlying neural tube closure.

    Evidence Zebrafish morpholino knockdown with NeoICD overexpression rescue, cell transplantation, microtubule immunostaining

    PMID:31399534

    Open questions at the time
    • Nuclear targets of NeoICD during neurulation not identified
    • Whether this cleavage event is regulated by specific proteases beyond γ-secretase unknown
  14. 2021 High

    Cryo-EM and X-ray structures of the ternary NEO1–NET1–RGM super-complex revealed that simultaneous ligand binding assembles a trimer-of-trimers that sterically prevents signaling-competent configurations of either pathway, explaining how netrin-1 silences RGMa repulsion and vice versa.

    Evidence Cryo-EM/X-ray crystallography of ternary complex, structure-guided mutagenesis, growth cone collapse and neuron migration assays

    PMID:33740419

    Open questions at the time
    • In vivo relevance of the super-complex at guidance decision points not demonstrated
    • Kinetics of complex assembly/disassembly unknown
  15. 2022 High

    Three studies expanded RGMa pathobiology: RGMa on neurons/astrocytes drives macrophage CXCL2 production via neogenin to recruit neutrophils in NMO; RGMa disrupts BBB integrity through BMP2/BMPRII/YAP-mediated tight junction loss; and RGMa promotes VSMC dedifferentiation via Slug to drive neointima formation—demonstrating breadth beyond axon guidance.

    Evidence Macrophage stimulation assay and NMO rat model with anti-RGMa mAb; HBMEC RGMa overexpression/knockdown with BMPRII inhibition and YAP activation; VSMC ox-LDL model with Slug siRNA rescue and carotid ligation in ApoE−/− mice

    PMID:35167145 PMID:35664003 PMID:36089003

    Open questions at the time
    • Whether CXCL2 regulation is Rap1-dependent or uses a distinct pathway unclear
    • BBB finding from a single lab awaits independent replication
    • VSMC dedifferentiation mechanism downstream of Slug not mapped
  16. 2023 High

    Demonstrating that RGMa collapses the neuronal actin barrier to promote uptake of misfolded SOD1, with anti-RGMa antibody reducing aggregation and symptoms in ALS mice, identified a novel cell-biological mechanism linking RGMa to proteinopathy spread.

    Evidence In vitro actin depolymerization and mutant SOD1 uptake assays with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model

    PMID:37992159

    Open questions at the time
    • Whether actin barrier collapse is neogenin-dependent not formally tested
    • Whether this mechanism generalizes to other misfolded proteins (e.g. TDP-43, α-synuclein) unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how cells coordinate the three major RGMa signaling modes (neogenin repulsion, BMP co-receptor, TGFβ/ALK5 scaffolding) in a context-dependent manner; the precise protease(s) and regulation of RGMa fragment balance in vivo; nuclear targets of NeoICD beyond LMO4; and whether the structural super-complex architecture with netrin-1 operates at in vivo guidance decision points.
  • No unified model for how cells select among parallel RGMa signaling outputs
  • In vivo fragment-specific signaling not mapped at single-cell resolution
  • Therapeutic antibodies target total RGMa—fragment-selective approaches not developed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ALK5BMP2BMP4LARGLMO4NEO1NTN1SLUG
Complex memberships
NEO1-RGMa-NET1 ternary super-complexRGMa-ALK5-Smad2/3 complexRGMa-BMP-BMPRI co-receptor complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 RGMa is a membrane-associated GPI-anchored glycoprotein that acts as a repulsive guidance molecule for retinal axons; recombinant RGMa at low nanomolar concentrations induces collapse of temporal (but not nasal) growth cones and repels temporal retinal axons in vitro, demonstrating axon-specific repulsive activity. In vitro growth cone collapse assay, stripe assay with recombinant RGMa protein, retinal axon guidance assay Nature High 12353034
2004 RGMa signals through the transmembrane receptor neogenin to mediate repulsive axon guidance. Neogenin overexpression or RGMa downregulation in the chick neural tube induces apoptosis; neogenin functions as a dependence receptor that induces cell death in the absence of RGMa, while RGMa binding to neogenin inhibits this pro-apoptotic activity. Neogenin pro-apoptotic activity is associated with caspase-mediated cleavage of its cytoplasmic domain. In ovo gene transfer (overexpression and knockdown), immortalized neuronal cell apoptosis assays, caspase cleavage assays Nature cell biology High 15258591
2004 RGMa is required for cephalic neural tube closure in mice, establishing an in vivo developmental role; mRGMa exhibits proteolytic processing and differential GPI-anchor-dependent cell-surface targeting. mRGMa is not required for anteroposterior topographic mapping of retinal ganglion cell axons to the superior colliculus. Mouse knockout (loss-of-function), in situ hybridization, biochemical processing analysis The Journal of neuroscience High 14749425
2004 RGMa acts as a repulsive signal in the developing dentate gyrus: it is expressed in the inner molecular layer and repels entorhinal axons, restricting them to the outer molecular layer. Neutralizing RGMa antibody or GPI anchor digestion with phosphatidylinositol-specific phospholipase C disrupts laminar termination of the perforant pathway in entorhino-hippocampal cocultures. Stripe assay, explant outgrowth assay, entorhino-hippocampal cocultures with neutralizing antibody and enzymatic GPI anchor removal The Journal of neuroscience High 15084667
2005 RGMa functions as a BMP co-receptor: the extracellular domain of RGMa directly binds BMP-2 and BMP-4 (but not TGF-β), forms a complex with BMP type I receptors, enhances BMP (but not TGF-β) signaling through the Smad1/5/8 pathway, and upregulates endogenous Id1 protein in cell culture. Radiolabeled BMP binding assay, co-immunoprecipitation with BMP type I receptors, Smad phosphorylation assay, Id1 western blot, cell-based reporter assays The Journal of biological chemistry High 15975920
2006 RGMa inhibits CNS neurite outgrowth through a mechanism dependent on activation of the RhoA–Rho kinase pathway. RGMa expression is induced in oligodendrocytes, myelinated fibers, and neurons around the injury site after spinal cord injury; neutralizing antibody to RGMa promotes axonal growth of the corticospinal tract and functional recovery after thoracic hemisection. In vitro neurite outgrowth assay with RhoA pathway inhibitors, in vivo intrathecal antibody administration, axon tracing, behavioral testing The Journal of cell biology High 16585268
2007 RGMa-induced growth cone collapse via neogenin is mediated by activation of RhoA, Rho kinase (ROCK), and PKC, but is independent of BMP signaling. Neogenin-knockout DRG neurons show no RGMa-mediated growth cone collapse or RhoA activation; dominant-negative RhoA abolishes collapse whereas dominant-negative Rac1 does not. Netrin-1 reduces RGMa-mediated collapse. DRG neuron growth cone collapse assay, neogenin-/- mouse neurons, dominant-negative constructs, Rho GTPase inhibitor C3-transferase, Y-27632, Gö6976 pharmacological inhibition The Journal of biological chemistry High 17389603
2007 RGMa alters BMP type II receptor utilization: in cells without RGMa, BMP2/4 signal preferentially through BMPRII; when RGMa is expressed, ActRIIA is also utilized. In BMPRII-null cells, RGMa-mediated BMP signaling requires ActRIIA. RGMa bound radiolabeled BMP2 and BMP4 with Kd ~2.4 and ~1.4 nM respectively. Radiolabeled BMP binding assay (Kd determination), siRNA knockdown of individual type II receptors, BMP signaling reporter assays in BMPRII-null cells The Journal of biological chemistry High 17472960
2008 RGMa–Neogenin interactions are required for neural fold elevation and neural tube closure in Xenopus; loss of Neogenin disrupts the microtubule network within deep neuroepithelial cells, impairing radial intercalation, and also disrupts apicobasal polarity of the pseudostratified neuroepithelium. Neogenin and RGMa work in the same pathway to regulate cell polarity during neurulation. Morpholino knockdown in Xenopus, microtubule immunostaining, neural tube morphology analysis The Journal of neuroscience High 19036958
2009 RGMa binding to neogenin leads to inactivation of Ras via the GTPase-activating protein p120GAP. FAK phosphorylated at Tyr-397 normally sequesters p120GAP via its SH2 domain; RGMa stimulation causes FAK dephosphorylation at Tyr-397, releasing p120GAP to inactivate GTP-Ras. This leads to Akt inactivation; constitutively active Akt prevents RGMa-induced growth cone collapse. Knockdown of p120GAP blocks RGMa-induced collapse. Co-immunoprecipitation (FAK–p120GAP), RhoA/Rac/Cdc42 activity assays, siRNA knockdown, dominant-negative and constitutively active Akt constructs, growth cone collapse assay The Journal of neuroscience High 19458235
2011 Activated microglia upregulate RGMa expression following LPS stimulation and inhibit axonal growth and induce growth cone collapse through direct contact in a RGMa-dependent manner; RGMa-neutralizing antibodies or siRNA knockdown attenuates microglial inhibition of neurite outgrowth. In vivo, minocycline reduces microglial activation, decreases RGMa expression, and reduces corticospinal tract dieback after SCI. Microglia-neuron co-culture with direct contact, RGMa siRNA and neutralizing antibody, in vivo SCI mouse model with minocycline treatment, axon tracing PloS one High 21957482
2011 RGMa expressed on dendritic cells binds to neogenin on CD4+ T cells, activating small GTPase Rap1 and increasing T cell adhesion to ICAM-1. Neutralizing anti-RGMa antibodies attenuate EAE clinical symptoms and reduce CNS inflammatory cell invasion, and reduce T cell proliferation and pro-inflammatory cytokine (IFN-γ, IL-2, IL-4, IL-17) secretion. Co-culture binding assay (RGMa-expressing BMDCs and neogenin+ T cells), Rap1 activation assay, ICAM-1 adhesion assay, in vivo EAE model with antibody blockade, adoptive transfer experiments Nature medicine High 21423182
2011 RGMa inhibits leukocyte migration by contact repulsion and chemorepulsion through its receptor neogenin in a dose-dependent manner; systemic application of RGMa attenuates pro-inflammatory cytokine production and inflammatory cell infiltration in a peritonitis model. The anti-inflammatory effect of RGMa is absent in neogenin-mutant mice, establishing neogenin dependence. In vitro leukocyte migration assays, in vivo zymosan-A peritonitis model, neogenin gene-trap mutant mice Proceedings of the National Academy of Sciences High 21467223
2012 RGMa is proteolytically processed by the proprotein convertases Furin and SKI-1, combined with autocatalytic cleavage and a disulfide bridge, generating four membrane-bound and three soluble forms. Both N- and C-terminal RGMa fragments bind the same fibronectin-like domains of neogenin and block neurite outgrowth; Furin/SKI-1 cleavage is essential for neogenin-mediated outgrowth inhibition in vivo. Mass spectrometry to identify fragments, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants, neogenin domain binding assays Developmental cell High 22340500
2012 RGMa promotes cell migration and cell adhesion outside the nervous system in a neogenin-dependent, BMP-independent manner. The RGD motif of RGMa is required for cell migration, while the partial von Willebrand factor type D (vWF) domain is preferentially required for cell adhesion. Disruption of RGMa homeostasis in vivo causes major migration defects during Xenopus gastrulation. Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, morpholino knockdown and overexpression in vivo, neogenin dependence tests Molecular and cellular biology High 22215618
2012 RGMa inhibits axon growth by inducing phosphorylation of CRMP-2 via both Rho-kinase and GSK-3β signaling pathways; inhibitors of either kinase reverse RGMa-induced CRMP-2 phosphorylation and neurite retraction. In vivo knockdown of RGMa after MCAO/reperfusion reduces pCRMP-2 levels and improves axonal integrity. Primary cortical neuron neurite outgrowth assay with recombinant RGMa and kinase inhibitors (Y-27632, GSK-3β inhibitor), western blot for pCRMP-2, in vivo adenoviral RGMa knockdown in rat MCAO model Molecular neurobiology High 23275173
2013 Crystal structures of the NEO1 RGM-binding region and its complex with RGMB reveal a previously unknown protein fold for RGM and an autocatalytic cleavage mechanism. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner; this architecture is shared by all RGM–NEO1 complexes. X-ray crystallography of NEO1–RGMB complex, functional validation of autocatalytic cleavage, binding assays Science High 23744777
2013 RGMa accumulates on amyloid plaques in Alzheimer's disease brains. TGFβ1, Aβ1-40, and Aβ1-42 markedly upregulate RGMa expression in human astrocytes. Co-immunoprecipitation confirmed molecular interaction between RGMa and the C-terminal fragment β of amyloid precursor protein (APP). Recombinant RGMa protein binds amyloid plaques in situ. Co-immunoprecipitation (RGMa–APP CTFβ), in situ plaque binding assay with recombinant protein, astrocyte stimulation with cytokines and Aβ peptides, immunohistochemistry Neuropathology and applied neurobiology Medium 22582881
2015 C-RGMa and N-RGMa fragments activate two distinct intracellular pathways: C-RGMa uses LARG/Rho/Rock to inhibit axonal growth, whereas N-RGMa relies on γ-secretase cleavage of the neogenin intracellular domain to generate NeICD, which uses LMO4 to block growth. In the developing tectum, C-RGMa/LARG-PDZ and N-RGMa/NeICD overexpression produce distinct layer-specific axon targeting errors. In ovo electroporation of C- and N-RGMa constructs and dominant-negative LARG (LARG-PDZ), γ-secretase inhibitor treatment, NeICD overexpression, anterograde axon labeling in chick tectum Cell death and differentiation High 26292756
2018 RGMa promotes reactive astrogliosis and glial scar formation after stroke by forming a complex with TGFβ receptor ALK5 and Smad2/3; RGMa knockdown abrogates TGFβ1-induced ALK5–Smad2/3 interaction and subsequent Smad2/3 phosphorylation, blocking key steps of reactive astrogliosis including cellular hypertrophy, GFAP upregulation, migration, and CSPG secretion. TGFβ1 stimulates RGMa expression via ALK5. Co-immunoprecipitation (RGMa–ALK5–Smad2/3 complex), Smad2/3 phosphorylation assay, RGMa siRNA knockdown in primary astrocytes, in vivo rat MCAO model with RGMa genetic/pharmacologic inhibition Cell death and differentiation High 29396549
2019 RGMa-induced NEO1 glycosylation and intramembrane proteolysis generates a transient nuclear intracellular fragment (NeoICD); this proteolytic cleavage is essential for neurulation (NEC elongation) as partial rescue of Neo1a and Rgma knockdown embryos by NeoICD overexpression was demonstrated. Rgma/Neo1 signaling promotes microtubule-mediated neuroepithelial cell elongation cell-autonomously. Morpholino knockdown in zebrafish, cell transplantation, NeoICD overexpression rescue, microtubule immunostaining, glycosylation assays The Journal of neuroscience High 31399534
2021 Simultaneous binding of NET1 and RGMa to NEO1 forms a ternary NEO1-NET1-RGM complex that assembles into a 'trimer-of-trimers' super-assembly in the cell membrane, resulting in reciprocal silencing of both RGMa–NEO1-mediated repulsion (growth cone collapse) and NET1–NEO1-mediated attraction (neuron migration) by preventing signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering. Cryo-EM/X-ray structures of ternary NEO1-NET1-RGM complex, cell-based growth cone collapse assay, neuron migration assay, structure-guided mutagenesis Cell High 33740419
2022 RGMa signaling via neogenin on infiltrating macrophages directly regulates CXCL2 (a neutrophil chemoattractant) expression; RGMa-expressing neurons and astrocytes present ligand to neogenin-expressing macrophages in NMO lesions, driving neutrophil recruitment and astrocytopathy. Anti-RGMa antibody suppresses this pathway, reduces neutrophil infiltration, and ameliorates neuropathic pain. In vitro macrophage RGMa stimulation assay (CXCL2 measurement), NMO rat model with anti-RGMa mAb, immunohistochemistry, gene expression assays Annals of neurology High 35167145
2022 RGMa causes blood-brain barrier dysfunction in endothelial cells through BMP2/BMPRII/YAP signaling: RGMa overexpression in HBMECs increases BMPRII and decreases YAP, ZO-1, and claudin-5; inhibiting BMPRII or activating YAP on an RGMa knockdown background restores tight junction proteins, confirming the pathway order. Lentiviral RGMa overexpression and knockdown in HBMECs, permeability assays, western blot for ZO-1/claudin-5/YAP/BMPRII, EAE mouse model, pharmacological BMPRII inhibition and YAP activation Frontiers in immunology Medium 35664003
2023 RGMa promotes collapse of the neuronal actin barrier, facilitating cellular uptake of misfolded mutant SOD1 protein; anti-RGMa antibody inhibits actin depolymerization in motor neurons, reduces mutant SOD1 accumulation, and ameliorates clinical symptoms in mSOD1 ALS mice. RGMa concentration is elevated in CSF of ALS patients and mSOD1 mice. In vitro actin depolymerization assay, mutant SOD1 uptake assay with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model treatment, immunohistochemistry for SOD1 aggregates Science advances High 37992159
2009 RGMa interacts with neogenin to mediate axon guidance in the embryonic vertebrate forebrain; dosage-sensitive genetic interactions between neogenin, RGMa, and Netrin-1 in Xenopus demonstrate they act in the same pathway to guide dorsoventral brain axons. Morpholino loss-of-function in Xenopus, double/triple partial knockdowns (genetic epistasis), axon pathway analysis Developmental biology Medium 16836993
2009 Intraretinal RGMa expression on retinal ganglion cell axons is required for retino-tectal topographic mapping; overexpression or knockdown of RGMa in the eye using in ovo electroporation produces terminal zone abnormalities, premature arborization stalling, overshooting, aberrant axonal turns, and intraretinal pathfinding errors. In ovo electroporation (overexpression and RNAi knockdown), anterograde axon tracing in chick optic tectum, new RGMa monoclonal antibody characterization Molecular and cellular neurosciences High 18280178
2012 Surface plasmon resonance quantification reveals RGM family members exhibit differential binding kinetics for BMP ligands: RGMA has the lowest binding affinity for most BMPs tested (Kd ~14–83 nM for BMP4/BMP2), while none of the RGMs bind BMP9. RGMs preferentially bind BMP4 > BMP2 > BMP5/6/7. Surface plasmon resonance (quantitative binding kinetics) PloS one High 23029472
2017 Adeno-associated virus-mediated overexpression of RGMa in adult mouse midbrain dopaminergic neurons induces selective degeneration of substantia nigra dopaminergic neurons with microglia and astrocyte activation, accompanied by progressive movement disorder, establishing a causal role for RGMa dysregulation in dopaminergic neuron degeneration resembling Parkinson's disease. AAV-mediated targeted overexpression of RGMa in mouse substantia nigra neurons, behavioral testing (motor coordination), immunohistochemistry for DA neuron markers and glial activation, nigrostriatal integrity analysis The Journal of neuroscience High 28842419
2022 RGMa promotes dedifferentiation of contractile vascular smooth muscle cells into a macrophage-like phenotype by enhancing the function of transcription factor Slug; Slug knockdown reverses RGMa-overexpression-induced VSMC dedifferentiation. RGMa knockdown in vivo reduces neointima formation in ligated carotid arteries in ApoE-/- mice. RGMa siRNA knockdown and overexpression in ox-LDL-treated VSMCs, Slug siRNA rescue experiment, in vivo carotid artery ligation in ApoE-/- mice with RGMa knockdown, immunohistochemistry Journal of lipid research Medium 36089003

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 RGM is a repulsive guidance molecule for retinal axons. Nature 250 12353034
2006 RGMa inhibition promotes axonal growth and recovery after spinal cord injury. The Journal of cell biology 242 16585268
2004 RGM and its receptor neogenin regulate neuronal survival. Nature cell biology 224 15258591
2005 Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. The Journal of biological chemistry 158 15975920
2004 Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system. The Journal of neuroscience : the official journal of the Society for Neuroscience 158 14749425
2011 RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. Nature medicine 103 21423182
2006 Neogenin interacts with RGMa and netrin-1 to guide axons within the embryonic vertebrate forebrain. Developmental biology 102 16836993
2018 RGMa mediates reactive astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke. Cell death and differentiation 99 29396549
2009 The RGM/DRAGON family of BMP co-receptors. Cytokine & growth factor reviews 92 19897400
2005 Spinal cord injury-induced lesional expression of the repulsive guidance molecule (RGM). The European journal of neuroscience 92 15845084
2007 Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4. The Journal of biological chemistry 89 17472960
2011 Activated microglia inhibit axonal growth through RGMa. PloS one 88 21957482
2007 Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC. The Journal of biological chemistry 84 17389603
2004 Isolation and expression pattern of three mouse homologues of chick Rgm. Gene expression patterns : GEP 82 14678836
2004 The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 15084667
1991 The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. I. Induction of regulatory macrophages in normal mice by the in vivo administration of rGM-CSF. Journal of immunology (Baltimore, Md. : 1950) 73 1824777
2005 Rebamipide significantly inhibits indomethacin-induced mitochondrial damage, lipid peroxidation, and apoptosis in gastric epithelial RGM-1 cells. Digestive diseases and sciences 70 16184425
2004 Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene expression patterns : GEP 68 15053976
2017 RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Scientific reports 67 28874746
1992 Haemopoietic cell kinetics in humans treated with rGM-CSF. International journal of cancer 65 1370226
2018 Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biological psychiatry 59 29478698
2011 Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation. Proceedings of the National Academy of Sciences of the United States of America 59 21467223
1989 The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) on 3'-azido-3'-deoxythymidine (AZT)-mediated biochemical and cytotoxic effects on normal human myeloid progenitor cells. Experimental hematology 59 2783247
2010 RGMA and IL21R show association with experimental inflammation and multiple sclerosis. Genes and immunity 57 20072140
2013 Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub. Science (New York, N.Y.) 55 23744777
2012 SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth. Developmental cell 52 22340500
2012 Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). PloS one 51 23029472
1987 Patterns of acute myeloid leukemia colony growth in response to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Experimental hematology 47 3496234
2014 RGM regulates BMP-mediated secondary axis formation in the sea anemone Nematostella vectensis. Cell reports 45 25482565
2009 Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms. Gastroenterology 45 19303019
2009 Inactivation of Ras by p120GAP via focal adhesion kinase dephosphorylation mediates RGMa-induced growth cone collapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 19458235
2008 Neogenin and RGMa control neural tube closure and neuroepithelial morphology by regulating cell polarity. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 19036958
2007 Role of RGM coreceptors in bone morphogenetic protein signaling. Journal of molecular signaling 43 17615080
2019 Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 30798120
2007 Neoplastic transformation and induction of H+,K+ -adenosine triphosphatase by N-methyl-N'-nitro-N-nitrosoguanidine in the gastric epithelial RGM-1 cell line. In vitro cellular & developmental biology. Animal 41 18034283
2010 The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway in Caenorhabditis elegans. Development (Cambridge, England) 38 20534671
2021 Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling. Cell 36 33740419
2009 Expression of the repulsive guidance molecule RGM and its receptor neogenin after spinal cord injury in sea lamprey. Experimental neurology 36 19268666
2019 MicroRNA-4472 Promotes Tumor Proliferation and Aggressiveness in Breast Cancer by Targeting RGMA and Inducing EMT. Clinical breast cancer 34 31899158
2017 The roles of RGMa-neogenin signaling in inflammation and angiogenesis. Inflammation and regeneration 34 29259705
2015 The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit. Stem cells (Dayton, Ohio) 34 25308084
1992 Monocyte-derived macrophage function in HIV-infected subjects: in vitro modulation by rIFN-gamma and rGM-CSF. Clinical immunology and immunopathology 34 1730155
2020 Delayed administration of the human anti-RGMa monoclonal antibody elezanumab promotes functional recovery including spontaneous voiding after spinal cord injury in rats. Neurobiology of disease 32 32590037
2013 Effective neuroprotection by ischemic postconditioning is associated with a decreased expression of RGMa and inflammation mediators in ischemic rats. Neurochemical research 32 23389659
2013 Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: a possible hallmark of regenerative failure in Alzheimer's disease brains. Neuropathology and applied neurobiology 31 22582881
2010 The repulsive guidance molecule, RGMa, promotes retinal ganglion cell survival in vitro and in vivo. Neuroscience 31 20457227
2020 Silencing miR-20a-5p inhibits axonal growth and neuronal branching and prevents epileptogenesis through RGMa-RhoA-mediated synaptic plasticity. Journal of cellular and molecular medicine 30 32779334
2013 The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans. Development (Cambridge, England) 29 24004951
2012 Minocycline promotes axonal regeneration through suppression of RGMa in rat MCAO/reperfusion model. Synapse (New York, N.Y.) 29 23184880
2018 Adenoviral vector-induced silencing of RGMa attenuates blood-brain barrier dysfunction in a rat model of MCAO/reperfusion. Brain research bulletin 28 29935233
2012 CRMP-2 is involved in axon growth inhibition induced by RGMa in vitro and in vivo. Molecular neurobiology 28 23275173
2017 Repulsive Guidance Molecule a (RGMa) Induces Neuropathological and Behavioral Changes That Closely Resemble Parkinson's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 28842419
2010 Characterization of the netrin/RGMa receptor neogenin in neurogenic regions of the mouse and human adult forebrain. The Journal of comparative neurology 25 20575069
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2007 RGMa inhibits neurite outgrowth of neuronal progenitors from murine enteric nervous system via the neogenin receptor in vitro. Journal of neurochemistry 24 17953666
2019 MicroRNA-210-3p Targets RGMA to Enhance the Angiogenic Functions of Endothelial Progenitor Cells Under Hypoxic Conditions. Frontiers in cellular neuroscience 22 31164807
2013 RGMa regulates cortical interneuron migration and differentiation. PloS one 21 24312340
2021 Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer. Oncogene 20 34754080
2019 Performance of RGM Medium for Isolation of Nontuberculous Mycobacteria from Respiratory Specimens from Non-Cystic Fibrosis Patients. Journal of clinical microbiology 20 30487305
2018 Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica. Scientific reports 20 29311561
1993 Modulation of macrophage Fc gamma receptors by rGM-CSF. Experimental hematology 20 8417954
2022 RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO. Annals of neurology 19 35167145
2016 Lentiviral Vector-Induced Overexpression of RGMa in the Hippocampus Suppresses Seizures and Mossy Fiber Sprouting. Molecular neurobiology 18 26843113
2013 Inhibition of repulsive guidance molecule, RGMa, increases afferent synapse formation with auditory hair cells. Developmental neurobiology 18 24123853
2012 Novel roles of the chemorepellent axon guidance molecule RGMa in cell migration and adhesion. Molecular and cellular biology 18 22215618
2007 Overexpression of repulsive guidance molecule (RGM) a induces cell death through Neogenin in early vertebrate development. Journal of molecular histology 18 17823845
2014 Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model. Molecular medicine reports 17 25420768
2012 Repulsive guidance molecule A (RGMa): a molecule for all seasons. Cell adhesion & migration 17 22568948
2008 Repulsive guidance molecule A (RGM A) and its receptor neogenin during neural and neural crest cell development of Xenopus laevis. Biology of the cell 17 18479252
1991 Effects of rGM-CSF and rG-CSF on the cisplatin sensitivity of the blast cells of acute myeloblastic leukemia. Leukemia 17 1707468
2015 ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum. Cell death and differentiation 16 26292756
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2022 Delayed administration of elezanumab, a human anti-RGMa neutralizing monoclonal antibody, promotes recovery following cervical spinal cord injury. Neurobiology of disease 15 35810963
2009 Sustained in vivo inhibition of protein domains using single-chain Fv recombinant antibodies and its application to dissect RGMa activity on axonal outgrowth. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 19176821
1998 Psoriasiform eruption triggered by recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) and exacerbated by granulocyte colony stimulating factor (rG-CSF) in a patient with breast cancer. Journal of Korean medical science 15 9886182
2022 RGMa Participates in the Blood-Brain Barrier Dysfunction Through BMP/BMPR/YAP Signaling in Multiple Sclerosis. Frontiers in immunology 14 35664003
2022 Modulation of Microglia M2 Polarization and Alleviation of Hippocampal Neuron Injury By MiR-106b-5p/RGMa in a Mouse Model of Status Epilepticus. Inflammation 14 35789312
2019 Rgma-Induced Neo1 Proteolysis Promotes Neural Tube Morphogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 31399534
2013 TFF1 is differentially expressed in stationary and migratory rat gastric epithelial cells (RGM-1) after in vitro wounding: influence of TFF1 RNA interference on cell migration. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 14 24107452
2011 Electrical stimulation of olfactory bulb downregulates RGMa expression after ischemia/reperfusion injury in rats. Brain research bulletin 14 21840379
2008 Intraretinal RGMa is involved in retino-tectal mapping. Molecular and cellular neurosciences 14 18280178
1989 Pluripotent hemopoietic stem cells give rise to osteoclasts in vitro: effects of rGM-CSF. Bone and mineral 14 2645966
2021 An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure. Scientific reports 13 33536466
2022 Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study. Neurocritical care 12 35028889
1992 Effect of bryostatin 1 on the in vitro radioprotective capacity of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) toward committed human myeloid progenitor cells (CFU-GM). Experimental hematology 12 1374343
2024 Circular RNA circHIPK2 inhibits colon cancer cells through miR-373-3p/RGMA axis. Cancer letters 11 38762192
2022 RGMa promotes dedifferentiation of vascular smooth muscle cells into a macrophage-like phenotype in vivo and in vitro. Journal of lipid research 11 36089003
2012 RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 11 23073896
1992 Response of CFU-GM (colony forming units for granulocytes and macrophages) from intact and pinealectomized rat bone marrow to murine recombinant interleukin-3 (rIl-3), recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) and human recombinant erythropoietin (rEPO). Progress in brain research 11 1410417
1992 Effects of bryostatin 1 and rGM-CSF on the metabolism of 1-beta-D-arabinofuranosylcytosine in human leukaemic myeloblasts. British journal of haematology 11 1486032
2023 RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science advances 10 37992159
2022 C-Phycocyanin and Lycium barbarum Polysaccharides Protect against Aspirin-Induced Inflammation and Apoptosis in Gastric RGM-1 Cells. Nutrients 10 36501143
2021 RGMa can induce skeletal muscle cell hyperplasia via association with neogenin signalling pathway. In vitro cellular & developmental biology. Animal 10 33748906
2020 Promoting functions of microRNA-29a/199B in neurological recovery in rats with spinal cord injury through inhibition of the RGMA/STAT3 axis. Journal of orthopaedic surgery and research 10 32948213
2022 Genomic and Experimental Analysis of the Insecticidal Factors Secreted by the Entomopathogenic Fungus Beauveria pseudobassiana RGM 2184. Journal of fungi (Basel, Switzerland) 9 35330256
2020 Evaluation of soluble expression of recombinant granulocyte macrophage stimulating factor (rGM-CSF) by three different E. coli strains. Research in pharmaceutical sciences 9 33088322
2016 A novel role for RGMa in modulation of bone marrow-derived dendritic cells maturation induced by lipopolysaccharide. International immunopharmacology 9 26896667
2023 Neutralizing RGMa with Elezanumab Promotes Cerebroprotection and Recovery in Rabbit Middle Cerebral Artery Occlusion. Translational stroke research 8 37326791
2022 Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy. BMC genomics 8 35255809
2002 Effect of rebamipide on cell death induced by combined treatment of mild heat shock and quercetin in RGM-1 cells: a role for HSP70 induction. Pharmacology 8 11731719