Affinage

RGMA

Repulsive guidance molecule A · UniProt Q96B86

Length
450 aa
Mass
49.4 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGMa is a GPI-anchored, membrane-associated glycoprotein that functions as a repulsive guidance molecule, restricting axon growth and steering cell migration through its transmembrane receptor neogenin (PMID:12353034, PMID:17389603, PMID:15084667). Recombinant RGMa collapses growth cones and repels specific axon populations in vitro (PMID:12353034, PMID:15084667), and signals through neogenin via a RhoA–Rho kinase (ROCK)–PKC cascade that is independent of BMP signaling (PMID:17389603); downstream, RGMa–neogenin triggers FAK dephosphorylation, dissociation of p120GAP, and inactivation of Ras and Akt, while phosphorylating the cytoskeletal effector CRMP-2 to drive neurite retraction (PMID:19458235, PMID:23275173). Proteolytic processing by autocatalysis and the proprotein convertases Furin and SKI-1 generates membrane-bound and soluble N- and C-terminal fragments that bind the same fibronectin-like domains of neogenin and independently inhibit outgrowth; the C-terminal fragment acts through a LARG/Rho/ROCK pathway, while the N-terminal fragment requires γ-secretase cleavage of neogenin to liberate a nuclear intracellular domain that engages LMO4 (PMID:22340500, PMID:26292756). Beyond axon guidance, RGMa acts as a dependence-receptor ligand, suppressing neogenin's caspase-mediated pro-apoptotic activity (PMID:15258591), and is essential for neural tube closure, where RGMa–neogenin signaling and the proteolytically released neogenin intracellular domain drive neuroepithelial cell elongation and microtubule organization (PMID:14749425, PMID:19036958, PMID:31399534). RGMa also functions as a BMP co-receptor: its soluble ectodomain binds BMP-2 and BMP-4, recruits BMP type I receptors, alters type II receptor utilization, and enhances Smad1/5/8 signaling and Id1 induction (PMID:15975920, PMID:17472960, PMID:23029472). Crystallographic studies of RGM–NEO1 complexes define a conserved fold and an autocatalytic cleavage mechanism, and reveal that co-occupancy of neogenin by Netrin-1 and RGM assembles a 'trimer-of-trimers' super-complex that silences signaling (PMID:23744777, PMID:33740419). In injury and immune contexts, RGMa is upregulated after CNS injury and by activated microglia to inhibit axon regeneration via RhoA (PMID:16585268, PMID:21957482), drives reactive astrogliosis and glial scar formation by complexing with the TGFβ1 receptor ALK5 and Smad2/3 (PMID:29396549), and modulates immune cell behavior—activating Rap1 in T cells to promote ICAM-1 adhesion, suppressing leukocyte migration through neogenin, and driving macrophage CXCL2 expression for neutrophil recruitment (PMID:21423182, PMID:21467223, PMID:35167145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 High

    Established the founding identity of RGMa as a concentration-dependent, axon-type-specific repulsive guidance cue, defining the biological problem its mechanism must explain.

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

    PMID:12353034

    Open questions at the time
    • Receptor unidentified at this stage
    • Intracellular signaling not addressed
    • Specificity for temporal axons mechanistically unexplained
  2. 2004 High

    Identified neogenin as the RGMa receptor and revealed a dependence-receptor logic in which neogenin drives apoptosis unless engaged by RGMa, expanding RGMa's role beyond guidance to cell survival.

    Evidence In ovo gain/loss-of-function in chick neural tube, neuronal apoptosis and caspase cleavage assays

    PMID:15258591

    Open questions at the time
    • Downstream death effectors not fully mapped
    • Link between guidance and survival outputs unclear
  3. 2004 High

    Genetically defined RGMa's developmental requirement, showing it is essential for cephalic neural tube closure but dispensable for retinotopic mapping, and characterized its proteolytic processing and GPI anchoring.

    Evidence Mouse knockout with morphological phenotyping, in situ hybridization, biochemical processing analysis; entorhinal laminar repulsion in cocultures

    PMID:14749425 PMID:15084667

    Open questions at the time
    • Cellular mechanism of neural tube closure defect not resolved here
    • Functional role of distinct cleavage products unknown
  4. 2005 High

    Revealed a second signaling modality—RGMa as a BMP co-receptor—showing its ectodomain binds BMP-2/4 and enhances Smad1/5/8 signaling, distinguishing it from the neogenin/repulsion axis.

    Evidence Radiolabeled ligand binding, co-IP with BMP type I receptors, reporter assays, Smad/Id1 Western blots

    PMID:15975920

    Open questions at the time
    • In vivo relevance of BMP co-receptor role not established
    • Relationship to neogenin signaling unclear
  5. 2007 High

    Dissected the repulsive signaling cascade, demonstrating RGMa–neogenin activates RhoA/ROCK/PKC independently of BMP, and quantified BMP receptor usage, separating the two RGMa pathways mechanistically.

    Evidence Neogenin-knockout DRG neurons, GTPase pull-downs, dominant-negatives, pharmacological inhibitors, noggin; SPR binding and type II receptor siRNA/null cells

    PMID:17389603 PMID:17472960

    Open questions at the time
    • GEF linking neogenin to RhoA not identified
    • Physiological switch between BMP and repulsive modes unclear
  6. 2009 High

    Extended the repulsion pathway downstream of RhoA to FAK–p120GAP–Ras–Akt, explaining how growth cone collapse is coupled to inactivation of pro-survival/growth signaling.

    Evidence Co-IP, phospho-FAK Tyr-397 Western blot, p120GAP siRNA, constitutively active Akt, collapse assay

    PMID:19458235

    Open questions at the time
    • Temporal coordination with RhoA arm not resolved
    • Direct neogenin–FAK link not defined
  7. 2011 High

    Defined RGMa as an injury- and inflammation-associated repulsive cue and immune modulator, showing activated microglia upregulate RGMa to block regeneration and that RGMa controls T cell adhesion (Rap1/ICAM-1) and leukocyte migration through neogenin.

    Evidence Microglia-neuron co-culture with siRNA/antibody and SCI minocycline model; Rap1 pull-down and T cell adhesion; leukocyte migration and zymosan peritonitis in neogenin-KO mice; EAE

    PMID:21423182 PMID:21467223 PMID:21957482

    Open questions at the time
    • Distinct downstream effectors in immune vs neuronal cells not unified
    • Context determining pro- vs anti-inflammatory output unclear
  8. 2012 High

    Established that proteolytic processing by Furin/SKI-1 is essential for neogenin-mediated outgrowth inhibition and that N- and C-terminal fragments bind the same neogenin domains and act independently.

    Evidence Cleavage product characterization, furin/SKI-1 siRNA, in vivo electroporation, domain-deletion neogenin binding; Xenopus RGD/vWF domain mapping for migration vs adhesion

    PMID:22215618 PMID:22340500

    Open questions at the time
    • Why multiple fragments with overlapping binding exist unresolved
    • Regulation of cleavage in vivo unknown
  9. 2013 High

    Provided the structural basis of RGM–NEO1 signaling, revealing a novel RGM fold, autocatalytic cleavage mechanism, and pH-dependent conformational stabilization of paired neogenin receptors conserved across RGM family.

    Evidence X-ray crystallography of NEO1–RGMB complex with structural mutagenesis

    PMID:23744777

    Open questions at the time
    • Direct RGMa (vs RGMB) structure inferred by conservation
    • How clustering converts to intracellular signal not shown
  10. 2015 High

    Resolved how the two RGMa fragments produce distinct outputs, with C-RGMa using LARG/Rho/ROCK and N-RGMa requiring γ-secretase generation of NeICD acting via LMO4, linking proteolysis to divergent signaling.

    Evidence In ovo electroporation, dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression, axon growth assays

    PMID:26292756

    Open questions at the time
    • How fragment ratio is set in vivo unknown
    • Nuclear LMO4 transcriptional targets not defined
  11. 2018 High

    Identified a TGFβ arm in which RGMa complexes with ALK5/Smad2/3 to potentiate astrogliosis and glial scar formation after stroke, broadening RGMa's signaling partners beyond neogenin and BMP receptors.

    Evidence Co-IP with ALK5/Smad2/3, RGMa siRNA, TGFβ1-stimulated astrocytes, rat MCAO model, p-Smad2/3 Western blots

    PMID:29396549

    Open questions at the time
    • Whether complex requires neogenin not addressed
    • Direct vs indirect ALK5 association unresolved
  12. 2021 High

    Revealed a structural signal-silencing mechanism in which co-binding of Netrin-1 and RGM to NEO1 assembles a 'trimer-of-trimers' super-complex that prevents signaling-competent receptor clustering, explaining ligand integration at neogenin.

    Evidence Crystal/structural analysis of NEO1–NET1–RGM ternary and super-complex, growth cone collapse and neuron migration assays

    PMID:33740419

    Open questions at the time
    • In vivo prevalence of super-complex unknown
    • Regulation of relative ligand concentrations unclear
  13. 2022 Medium

    Mapped additional context-specific RGMa functions in disease tissues—macrophage CXCL2-driven neutrophil recruitment in NMO, VSMC dedifferentiation via Slug, and BBB dysfunction via BMP2/BMPRII/YAP.

    Evidence NMO rat model with anti-RGMa antibody and macrophage assays; VSMC siRNA/overexpression and ApoE-/- carotid ligation; HBMEC overexpression/knockdown with pathway pharmacology

    PMID:35167145 PMID:35664003 PMID:36089003

    Open questions at the time
    • Each mechanism shown by single lab
    • Receptor identity in non-neuronal contexts variably defined
  14. 2023 Medium

    Linked RGMa to actin cytoskeletal regulation in motor neurons, showing it promotes actin depolymerization to facilitate mutant SOD1 uptake, connecting RGMa to ALS pathology.

    Evidence In vitro uptake assay with anti-RGMa antibody, mSOD1 mouse histochemistry, CSF RGMa, behavioral testing

    PMID:37992159

    Open questions at the time
    • Single lab
    • Receptor mediating actin effect not defined
    • Mechanistic link to RhoA pathway unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGMa selects among its multiple signaling modalities (neogenin repulsion, BMP co-receptor, ALK5/TGFβ potentiation) in a given cell, and how proteolytic fragment ratios and ligand competition are regulated in vivo, remains unresolved.
  • No unified model linking fragment generation to pathway choice
  • In vivo regulation of competing ligands at neogenin unknown
  • Transcriptional outputs of nuclear NeICD/LMO4 axis uncharacterized

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:0060089 molecular transducer activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 GO:0140096 catalytic activity, acting on a protein 2
Partners
ALK5APPBMP2BMP4NEO1NET1
Complex memberships
NEO1–NET1–RGM ternary super-complexRGMa–ALK5–Smad2/3 complexRGMa–BMP type I receptor complexRGMa–neogenin (NEO1) complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 RGMa (originally called RGM) is a membrane-associated glycoprotein that acts as a repulsive guidance molecule: recombinant RGMa at low nanomolar concentration induces collapse of temporal retinal growth cones and repels temporal retinal axons in vitro, with activity restricted to temporal (not nasal) axons, establishing its repulsive, axon-specific guiding function. In vitro growth cone collapse assay and stripe/outgrowth assay with recombinant RGMa protein Nature High 12353034
2004 RGMa signals through the transmembrane receptor neogenin: neogenin overexpression or RGMa downregulation in the chick neural tube induces apoptosis; neogenin acts as a dependence receptor that induces cell death in the absence of RGMa, while RGMa binding to neogenin inhibits this pro-apoptotic activity. Neogenin's pro-apoptotic activity is associated with caspase-mediated cleavage of its cytoplasmic domain. In ovo gene transfer (overexpression/knockdown), immortalized neuronal cell apoptosis assay, caspase cleavage analysis Nature cell biology High 15258591
2005 RGMa functions as a BMP co-receptor: the soluble extracellular domain of RGMa (RGMa.Fc) directly and selectively binds radiolabeled BMP-2 and BMP-4, forms a complex with BMP type I receptors, enhances BMP (but not TGF-β) signaling in a ligand-dependent manner in cell culture, signals through the classical Smad1/5/8 pathway, and upregulates the downstream target Id1 protein. Radiolabeled ligand binding assay, co-immunoprecipitation with BMP type I receptors, cell-based BMP signaling reporter assay, Western blot for Smad phosphorylation and Id1 The Journal of biological chemistry High 15975920
2004 mRGMa is required for cephalic neural tube closure in mice (loss-of-function knockout mice show neural tube defects), but mRGMa is not required for anteroposterior topographic targeting of retinal ganglion cell axons to the superior colliculus. Mouse RGMa proteins share proteolytic processing but differ in GPI anchor addition compared to homologs. Mouse knockout (loss-of-function genetic study), in situ hybridization for expression, biochemical characterization of processing The Journal of neuroscience High 14749425
2006 RGMa inhibits CNS neurite outgrowth via a mechanism dependent on activation of the RhoA–Rho kinase pathway. RGMa is expressed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is upregulated at the injury site after spinal cord injury. Intrathecal administration of a neutralizing anti-RGMa antibody promotes axonal growth of the corticospinal tract and improves functional recovery after thoracic hemisection. In vitro neurite outgrowth assay with RhoA pathway inhibitors, immunohistochemistry for RGMa expression, intrathecal antibody administration in rat SCI model with axon tracing and behavioral assessment The Journal of cell biology High 16585268
2007 RGMa-neogenin-induced growth cone collapse is mediated by activation of RhoA, Rho kinase (ROCK), and PKC, and is independent of BMP signaling. In neogenin-knockout DRG neurons, RGMa fails to collapse growth cones or activate RhoA. Soluble RGMa activates RhoA within 3 minutes in wild-type neurons; Rac1 and Cdc42 are unaffected. Dominant-negative RhoA abolishes collapse; BMP antagonist noggin has no effect. DRG cultures from neogenin-/- mice, RhoA/Rac1/Cdc42 pull-down activation assays, pharmacological inhibitors (C3-transferase, Y-27632, Gö6976), dominant-negative constructs, noggin pretreatment The Journal of biological chemistry High 17389603
2007 RGMa alters BMP type II receptor utilization: RGMa binds BMP2 and BMP4 with Kd values of ~2.4 nM and ~1.4 nM respectively. In cells expressing RGMa, BMP2/4 signaling utilizes both BMPRII and ActRIIA, whereas without RGMa, only BMPRII is required. In BmpRII-null cells, RGMa-mediated BMP signaling requires ActRIIA. Surface plasmon resonance / radiolabeled binding assay, siRNA knockdown of individual type II receptors, BmpRII-null cell lines, BMP reporter assays The Journal of biological chemistry High 17472960
2009 RGMa binding to neogenin leads to inactivation of Ras via the GTPase-activating protein p120GAP. RGMa stimulation causes FAK dephosphorylation at Tyr-397, dissociation of p120GAP from FAK, and subsequent increase in p120GAP–GTP-Ras interaction. p120GAP knockdown prevents RGMa-induced growth cone collapse. RGMa further inactivates Akt downstream of Ras; constitutively active Akt blocks RGMa-induced collapse. Co-immunoprecipitation, phospho-specific Western blot for FAK Tyr-397, siRNA knockdown of p120GAP, dominant-negative/constitutively active Akt expression, growth cone collapse assay The Journal of neuroscience High 19458235
2011 RGMa mediates activated microglia-induced inhibition of axonal growth. LPS-activated microglia increase RGMa expression and directly inhibit neurite outgrowth and induce growth cone collapse in cortical neurons via cell contact; neutralizing anti-RGMa antibodies or RGMa siRNA attenuate this inhibition. In a mouse SCI model, minocycline reduces microglial activation, decreases RGMa expression, and reduces corticospinal tract dieback. In vitro microglia-neuron co-culture with LPS activation, neutralizing antibody and siRNA knockdown of RGMa, in vivo mouse SCI with minocycline treatment and axon tracing PloS one High 21957482
2011 RGMa binding to CD4+ T cells (which express the neogenin receptor) activates the small GTPase Rap1 and increases T cell adhesion to ICAM-1. RGMa expressed by dendritic cells modulates T cell activation; anti-RGMa antibody reduces T cell proliferation and cytokine secretion (IFN-γ, IL-2, IL-4, IL-17) and attenuates EAE. In vivo, anti-RGMa antibody reduces inflammatory cell invasion into the CNS. Rap1 activation assay (pull-down), T cell adhesion assay, RGMa siRNA knockdown in dendritic cells, adoptive transfer EAE model, neutralizing antibody treatment in vivo Nature medicine High 21423182
2011 RGMa inhibits leukocyte migration by contact repulsion and chemorepulsion through its receptor neogenin in a dose-dependent manner. Systemic RGMa application suppresses the inflammatory response (reduces TNF-α, IL-6, MIP-1α, inflammatory cell infiltration, and edema) in a zymosan-A peritonitis model. This anti-inflammatory effect is absent in neogenin-deficient (neo1 gene-trap) mice. In vitro leukocyte migration assay, in vivo zymosan peritonitis model, neogenin knockout (gene-trap) mice, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 21467223
2012 RGMa is proteolytically processed by the proprotein convertases Furin and SKI-1 (in addition to autocatalytic cleavage and a disulfide bridge) to generate four membrane-bound and three soluble forms. Proteolytic cleavage of RGMa is essential for neogenin-mediated outgrowth inhibition in vivo. Both N- and C-terminal RGMa fragments bind the same fibronectin-like domains in neogenin and independently block axonal outgrowth. Biochemical characterization of RGMa cleavage products, furin/SKI-1 siRNA knockdown, in vivo electroporation assay for axon guidance, domain-deletion binding assays with neogenin Developmental cell High 22340500
2013 Crystal structure of the NEO1 RGM-binding region in complex with RGMB reveals: (1) a previously unknown RGM protein fold; (2) a functionally important autocatalytic cleavage mechanism in RGM; (3) in the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner; (4) all RGM–NEO1 complexes share this architecture. This structural framework also explains disease-linked RGM mutations. X-ray crystallography, structural mutagenesis, functional validation of complex assembly Science High 23744777
2012 RGMa promotes cortical interneuron differentiation (potentiates neurite outgrowth) and acts as a chemorepulsive cue for newborn interneurons migrating out of the ganglionic eminence ventricular zone via neogenin. Simultaneous exposure to RGMa and Netrin-1 completely abrogates RGMa-induced chemorepulsion, revealing signal integration between these two neogenin ligands. In vitro explant migration assay, Neogenin receptor blocking, RGMa/Netrin-1 gradient co-exposure, neurite outgrowth assay PloS one Medium 24312340
2018 RGMa promotes reactive astrogliosis and glial scar formation after stroke by forming a co-immunoprecipitable complex with the TGFβ1 receptor ALK5 and Smad2/3. This complex facilitates ALK5–Smad2/3 interaction and phosphorylation of Smad2/3 downstream of TGFβ1. TGFβ1 stimulates RGMa expression via ALK5. RGMa knockdown abrogates TGFβ1-induced astrogliosis, cellular hypertrophy, GFAP upregulation, cell migration, and CSPG secretion. Co-immunoprecipitation of RGMa with ALK5 and Smad2/3, RGMa knockdown (siRNA), TGFβ1 stimulation of primary astrocytes, in vivo rat MCAO model with genetic/pharmacologic inhibition, Western blot for p-Smad2/3 Cell death and differentiation High 29396549
2015 Two RGMa peptide fragments (N-RGMa and C-RGMa) activate distinct intracellular pathways for axonal growth inhibition in the optic tectum. C-RGMa activates a LARG (Leukemia-associated RhoGEF)/Rho/ROCK pathway. N-RGMa requires γ-secretase cleavage of neogenin's intracellular portion to generate NeICD, which uses LIM-only protein 4 (LMO4) to block growth. Overexpression of C-RGMa and dominant-negative LARG induced tectal axon layer-targeting defects in vivo. In ovo electroporation (gain/loss-of-function), dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression, in vitro axon growth assays Cell death and differentiation High 26292756
2012 RGMa promotes cell migration and adhesion in a neogenin-dependent, BMP-independent manner. Specific domains mediate distinct functions: the RGD motif is required for RGMa-stimulated cell migration, while the partial von Willebrand factor type D (vWF) domain is preferentially required for cell adhesion. In vivo loss of RGMa or its overexpression in Xenopus causes major gastrulation migration defects. Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, neogenin morpholino knockdown, BMP inhibitor (noggin), in vivo morpholino knockdown of RGMa Molecular and cellular biology Medium 22215618
2006 Neogenin acts as an axon guidance receptor in vivo, binding both RGMa (chemorepulsive) and Netrin-1 (chemoattractive) to guide axons in the embryonic Xenopus forebrain. Simultaneous partial knockdown of neogenin with either RGMa or Netrin-1 reveals dosage-sensitive interactions, indicating they act in the same guidance pathway. Morpholino knockdown in Xenopus, axon tract analysis, double knockdown epistasis experiments Developmental biology Medium 16836993
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 neural plate cells and blocks radial intercalation needed for neural fold elevation. Sustained neogenin activity is also required for establishment of the apicobasally polarized pseudostratified neuroepithelium. Morpholino knockdown of RGMa and neogenin in Xenopus, immunofluorescence of microtubule network, neural tube morphology analysis The Journal of neuroscience Medium 19036958
2019 RGMa-induced neogenin proteolysis (glycosylation and intramembrane cleavage) produces a transient nuclear intracellular domain (NeoICD) that is required for neuroepithelial cell elongation and neural tube morphogenesis in zebrafish. NeoICD overexpression partially rescues Neo1a and Rgma knockdown phenotypes. This pathway promotes NEC elongation independently of establishment of apical junctional complexes. Zebrafish morpholino knockdown, cell transplantation for cell autonomy, NeoICD overexpression rescue, immunofluorescence for microtubules and junctional complexes The Journal of neuroscience Medium 31399534
2012 CRMP-2 (collapsin response mediator protein-2) is a downstream mediator of RGMa-induced axon growth inhibition. RGMa induces CRMP-2 phosphorylation (neurite retraction) in vitro, which is reversed by inhibitors of Rho-kinase (Y-27632) or GSK-3β. In a rat MCAO/reperfusion model, knockdown of RGMa by adenoviral shRNA reduces pCRMP-2 levels and improves axonal integrity. Primary cortical neuron culture with recombinant RGMa and kinase inhibitors, Western blot for pCRMP-2, adenoviral RGMa shRNA in vivo, NF-200 immunostaining Molecular neurobiology Medium 23275173
2021 Simultaneous binding of NET1 (Netrin-1) and RGMa to NEO1 forms a ternary NEO1–NET1–RGM complex that assembles into a 'trimer-of-trimers' super-assembly in the cell membrane. Formation of this super-complex inhibits RGMA–NEO1-mediated growth cone collapse and RGMA- or NET1-NEO1-mediated neuron migration, by preventing signaling-competent RGM–NEO1 complexes and NET1-induced NEO1 ectodomain clustering. Crystal structure of NEO1–NET1–RGM ternary complex, cryo-EM or structural analysis of super-assembly, growth cone collapse assay, neuron migration assay Cell High 33740419
2023 RGMa promotes actin depolymerization in motor neurons, collapsing the neuronal actin barrier and facilitating cellular uptake of mutant SOD1 protein. Anti-RGMa monoclonal antibody inhibits actin depolymerization, reduces mutant SOD1 accumulation in motor neurons of mSOD1 mice, and ameliorates clinical symptoms. RGMa is elevated in CSF of ALS patients and mSOD1 mice. In vitro cellular uptake assay with anti-RGMa antibody, histochemical analysis of actin and mutant SOD1 in mSOD1 mouse spinal cord, CSF RGMa measurement, behavioral testing Science advances Medium 37992159
2013 RGMa co-immunoprecipitates with the C-terminal fragment β of amyloid precursor protein (APP), and recombinant RGMa protein binds amyloid plaques in situ. TGFβ1, Aβ1-40, and Aβ1-42 markedly elevate RGMa levels in human astrocytes, suggesting upstream regulation of RGMa by amyloid-related signals. Co-immunoprecipitation of RGMa with APP C-terminal fragment, in situ binding of recombinant RGMa to amyloid plaques, TGFβ1/Aβ treatment of primary human astrocytes with Western blot Neuropathology and applied neurobiology Low 22582881
2022 RGMa–neogenin signaling in infiltrating macrophages (which express neogenin) drives CXCL2 expression, promoting neutrophil chemoattraction and astrocytopathy in NMO lesions. In vitro experiments confirmed that RGMa directly regulates CXCL2 expression in macrophages. In vivo NMO rat model with anti-RGMa monoclonal antibody treatment, immunohistochemistry for macrophage neogenin and CXCL2, in vitro macrophage RGMa stimulation assay, gene expression analysis Annals of neurology Medium 35167145
2022 RGMa promotes vascular smooth muscle cell (VSMC) dedifferentiation into a macrophage-like phenotype via enhancement of the transcription factor Slug. RGMa mRNA and protein increase in ox-LDL-induced VSMCs. Slug knockdown reverses RGMa-overexpression-promoted dedifferentiation. RGMa knockdown in vivo reduces neointima formation in ligated carotid arteries of ApoE-/- mice. siRNA knockdown of RGMa and Slug in VSMCs, RGMa overexpression, ox-LDL stimulation, in vivo carotid ligation model in ApoE-/- mice, Western blot for VSMC/macrophage markers Journal of lipid research Medium 36089003
2009 RGMa is expressed in the adult rat spinal cord in oligodendrocytes, myelinated fibers, and neurons, and co-localizes with RhoA in lesional retraction bulbs after spinal cord injury, providing evidence that RGMa exerts growth-inhibitory effects via the RhoA second messenger system at injury sites. Immunohistochemistry with cell-type markers and RhoA co-staining in rat SCI tissue sections The European journal of neuroscience Low 15845084
2012 Surface plasmon resonance quantitation shows that RGMA binds BMP4 and BMP2 with Kd values of ~14 nM and ~22 nM respectively, while exhibiting lower affinity than RGMB and HJV for most BMPs; RGMA does not bind BMP9. RGMA shows lowest relative affinity among RGM family members for most BMPs tested. Surface plasmon resonance (SPR) binding kinetics PloS one High 23029472
2004 RGMa acts as a repulsive signal for entorhinal axons, confining them to the outer molecular layer of the dentate gyrus. In stripe and outgrowth assays, entorhinal axons are repelled by recombinant RGMa. Disruption of RGMa function (neutralizing antibody or GPI-anchor cleavage by PI-PLC) causes loss of the specific laminar termination pattern in entorhino-hippocampal cocultures. Stripe assay, explant outgrowth assay, entorhino-hippocampal coculture with neutralizing antibody and PI-PLC treatment The Journal of neuroscience High 15084667
2016 RGMa overexpression in the hippocampus suppresses seizures, reduces mossy fiber sprouting, and inhibits hyperexcitability of hippocampal neurons by suppressing NMDAR-mediated currents in an organotypic slice model. RGMa expression is decreased in TLE patients and epileptic animal models. Lentiviral overexpression of RGMa in rat hippocampus, behavioral seizure assessment, Timm staining for mossy fiber sprouting, electrophysiology (NMDAR current recording) in organotypic slices Molecular neurobiology Medium 26843113
2017 Adeno-associated virus-mediated overexpression of RGMa in adult mouse dopaminergic neurons induces progressive degeneration of dopaminergic neurons in the substantia nigra, loss of DA release in the striatum, and a progressive movement disorder that models Parkinson's disease, accompanied by microglia and astrocyte activation. AAV-mediated overexpression of RGMa in mouse midbrain, behavioral testing (motor coordination), immunohistochemistry for dopaminergic markers, microglia/astrocyte activation assay The Journal of neuroscience Medium 28842419
2009 Intraretinal RGMa expression controls topographic targeting of retinal ganglion cell axons. Overexpression or knockdown of RGMa in the retina via in ovo electroporation causes abnormal retino-tectal projection phenotypes (absent terminal zones, premature stalling, overshooting, aberrant turns, deeper tectal layer projections, and intraretinal pathfinding errors). In ovo electroporation (overexpression/knockdown), anterograde labeling of retinal axons Molecular and cellular neurosciences Medium 18280178
2013 RGMa inhibits afferent synapse formation between auditory neurons and hair cells: blocking RGMa with a neutralizing antibody increases contact of neural processes with hair cells, increases postsynaptic densities at ribbon synapse sites, and accelerates pruning of auditory fibers to the mature branching pattern. In vitro cochlear explant culture with anti-RGMa blocking antibody, synapse quantification (confocal microscopy), morphometric analysis of fiber branching Developmental neurobiology Medium 24123853
2022 RGMa causes blood-brain barrier (BBB) dysfunction in endothelial cells via a BMP2/BMPRII/YAP signaling pathway, leading to downregulation of tight junction proteins ZO-1 and claudin-5. RGMa overexpression in HBMECs significantly increases BBB permeability; knockdown strengthens barrier integrity. BMPRII activation or YAP inhibition downstream of RGMa knockdown reverses the effect. Lentiviral RGMa overexpression/knockdown in HBMECs, BBB permeability assay, Western blot for ZO-1/claudin-5/YAP/BMP2/BMPRII, pharmacological BMPRII activator/inhibitor and YAP inhibitor/activator Frontiers in immunology Medium 35664003

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 101 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
2011 Activated microglia inhibit axonal growth through RGMa. PloS one 89 21957482
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
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 71 16184425
2017 RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Scientific reports 68 28874746
2004 Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene expression patterns : GEP 68 15053976
1992 Haemopoietic cell kinetics in humans treated with rGM-CSF. International journal of cancer 65 1370226
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 46 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
2021 Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling. Cell 38 33740419
2010 The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway in Caenorhabditis elegans. Development (Cambridge, England) 38 20534671
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
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 28 28842419
2012 CRMP-2 is involved in axon growth inhibition induced by RGMa in vitro and in vivo. Molecular neurobiology 28 23275173
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
1992 Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). A review of its pharmacological properties and prospective role in the management of myelosuppression. Drugs 25 1377118
2019 MicroRNA-210-3p Targets RGMA to Enhance the Angiogenic Functions of Endothelial Progenitor Cells Under Hypoxic Conditions. Frontiers in cellular neuroscience 24 31164807
2007 RGMa inhibits neurite outgrowth of neuronal progenitors from murine enteric nervous system via the neogenin receptor in vitro. Journal of neurochemistry 24 17953666
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
1992 Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF) : A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression. Drugs 17 28421558
1991 Effects of rGM-CSF and rG-CSF on the cisplatin sensitivity of the blast cells of acute myeloblastic leukemia. Leukemia 17 1707468
2022 Delayed administration of elezanumab, a human anti-RGMa neutralizing monoclonal antibody, promotes recovery following cervical spinal cord injury. Neurobiology of disease 16 35810963
2015 ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum. Cell death and differentiation 16 26292756
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
2024 Circular RNA circHIPK2 inhibits colon cancer cells through miR-373-3p/RGMA axis. Cancer letters 12 38762192
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
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
2022 C-Phycocyanin and Lycium barbarum Polysaccharides Protect against Aspirin-Induced Inflammation and Apoptosis in Gastric RGM-1 Cells. Nutrients 11 36501143
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 Genomic and Experimental Analysis of the Insecticidal Factors Secreted by the Entomopathogenic Fungus Beauveria pseudobassiana RGM 2184. Journal of fungi (Basel, Switzerland) 10 35330256
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 Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy. BMC genomics 9 35255809
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
2016 Effects of maternal lead exposure on RGMa and RGMb expression in the hippocampus and cerebral cortex of mouse pups. Brain research bulletin 8 27545491
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

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