{"gene":"RGMA","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"In vitro growth cone collapse assay and stripe/outgrowth assay with recombinant RGMa protein","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro functional assay with recombinant protein, foundational paper, multiple assays (collapse and stripe assay)","pmids":["12353034"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In ovo gene transfer (overexpression/knockdown), immortalized neuronal cell apoptosis assay, caspase cleavage analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function in vivo, replicated in cell lines, mechanistic cleavage data, multiple orthogonal methods","pmids":["15258591"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Radiolabeled ligand binding assay, co-immunoprecipitation with BMP type I receptors, cell-based BMP signaling reporter assay, Western blot for Smad phosphorylation and Id1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay, receptor complex co-IP, downstream pathway validation with multiple orthogonal methods in one study","pmids":["15975920"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Mouse knockout (loss-of-function genetic study), in situ hybridization for expression, biochemical characterization of processing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined morphological phenotype, replicated across multiple assays in single rigorous study","pmids":["14749425"],"is_preprint":false},{"year":2006,"finding":"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.","method":"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","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway (RhoA-ROCK) established in vitro, corroborated with in vivo loss-of-function antibody and defined phenotypic readout","pmids":["16585268"],"is_preprint":false},{"year":2007,"finding":"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.","method":"DRG cultures from neogenin-/- mice, RhoA/Rac1/Cdc42 pull-down activation assays, pharmacological inhibitors (C3-transferase, Y-27632, Gö6976), dominant-negative constructs, noggin pretreatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches (KO neurons, dominant negatives, pharmacological inhibitors, GTPase assays) in one rigorous study","pmids":["17389603"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Surface plasmon resonance / radiolabeled binding assay, siRNA knockdown of individual type II receptors, BmpRII-null cell lines, BMP reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative binding data plus genetic dissection of receptor usage with multiple cell lines and siRNA, multiple orthogonal methods","pmids":["17472960"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, phospho-specific Western blot for FAK Tyr-397, siRNA knockdown of p120GAP, dominant-negative/constitutively active Akt expression, growth cone collapse assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and genetic approaches in a single rigorous study establishing FAK-p120GAP-Ras-Akt pathway","pmids":["19458235"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — both in vitro mechanistic dissection (siRNA, antibody) and in vivo corroboration with defined phenotype","pmids":["21957482"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Rap1 activation assay (pull-down), T cell adhesion assay, RGMa siRNA knockdown in dendritic cells, adoptive transfer EAE model, neutralizing antibody treatment in vivo","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical (Rap1 pull-down, adhesion assay) and in vivo genetic/pharmacological evidence across multiple assays","pmids":["21423182"],"is_preprint":false},{"year":2011,"finding":"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.","method":"In vitro leukocyte migration assay, in vivo zymosan peritonitis model, neogenin knockout (gene-trap) mice, cytokine measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor dependence confirmed genetically with KO mice plus pharmacological in vitro and in vivo evidence","pmids":["21467223"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Biochemical characterization of RGMa cleavage products, furin/SKI-1 siRNA knockdown, in vivo electroporation assay for axon guidance, domain-deletion binding assays with neogenin","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical dissection of cleavage mechanism with functional in vivo validation and domain-mapping experiments","pmids":["22340500"],"is_preprint":false},{"year":2013,"finding":"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.","method":"X-ray crystallography, structural mutagenesis, functional validation of complex assembly","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation; establishes the structural basis of RGM-NEO1 signaling hub; applies to RGMA by demonstrated conservation","pmids":["23744777"],"is_preprint":false},{"year":2012,"finding":"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.","method":"In vitro explant migration assay, Neogenin receptor blocking, RGMa/Netrin-1 gradient co-exposure, neurite outgrowth assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays with clear mechanistic readouts (migration, outgrowth, receptor dependence), single lab","pmids":["24312340"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing complex, multiple functional readouts, in vivo and in vitro corroboration, mechanism-based rescue experiments","pmids":["29396549"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In ovo electroporation (gain/loss-of-function), dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression, in vitro axon growth assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual pathway dissection with genetic and pharmacological tools both in vitro and in vivo, multiple orthogonal methods","pmids":["26292756"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, neogenin morpholino knockdown, BMP inhibitor (noggin), in vivo morpholino knockdown of RGMa","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by deletion mutants with functional assays, neogenin dependence established, in vivo corroboration; single lab","pmids":["22215618"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Morpholino knockdown in Xenopus, axon tract analysis, double knockdown epistasis experiments","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function epistasis in Xenopus, dosage-sensitive interactions; single lab","pmids":["16836993"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Morpholino knockdown of RGMa and neogenin in Xenopus, immunofluorescence of microtubule network, neural tube morphology analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with cellular mechanistic readout (microtubule disruption), single lab","pmids":["19036958"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Zebrafish morpholino knockdown, cell transplantation for cell autonomy, NeoICD overexpression rescue, immunofluorescence for microtubules and junctional complexes","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo cell-autonomous function established by transplant, proteolytic mechanism with partial rescue; single lab","pmids":["31399534"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Primary cortical neuron culture with recombinant RGMa and kinase inhibitors, Western blot for pCRMP-2, adenoviral RGMa shRNA in vivo, NF-200 immunostaining","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway dissection with pharmacological inhibitors confirmed in vivo; single lab","pmids":["23275173"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Crystal structure of NEO1–NET1–RGM ternary complex, cryo-EM or structural analysis of super-assembly, growth cone collapse assay, neuron migration assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of ternary and super-complex combined with functional assays demonstrating signal silencing; multiple orthogonal methods","pmids":["33740419"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic (actin depolymerization) supported by in vitro and in vivo evidence with antibody intervention; single lab","pmids":["37992159"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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","journal":"Neuropathology and applied neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown, no functional validation of the RGMa-APP interaction consequence; single lab","pmids":["22582881"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic link (RGMa→CXCL2 in macrophages) corroborated in vivo with antibody intervention and defined phenotype; single lab","pmids":["35167145"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic dissection (Slug pathway) plus in vivo corroboration; single lab","pmids":["36089003"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Immunohistochemistry with cell-type markers and RhoA co-staining in rat SCI tissue sections","journal":"The European journal of neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization by IHC only, no direct functional manipulation; consistent with pathway placement but not mechanistically definitive","pmids":["15845084"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Surface plasmon resonance (SPR) binding kinetics","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro SPR binding assay with defined Kd values; single lab but rigorous biophysical method","pmids":["23029472"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Stripe assay, explant outgrowth assay, entorhino-hippocampal coculture with neutralizing antibody and PI-PLC treatment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro functional assays (stripe, outgrowth, coculture) using recombinant protein and two independent loss-of-function approaches","pmids":["15084667"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Lentiviral overexpression of RGMa in rat hippocampus, behavioral seizure assessment, Timm staining for mossy fiber sprouting, electrophysiology (NMDAR current recording) in organotypic slices","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with defined phenotype plus in vitro electrophysiology; single lab","pmids":["26843113"],"is_preprint":false},{"year":2017,"finding":"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.","method":"AAV-mediated overexpression of RGMa in mouse midbrain, behavioral testing (motor coordination), immunohistochemistry for dopaminergic markers, microglia/astrocyte activation assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in vivo with defined neurodegeneration phenotype; single lab, no mechanistic pathway placement beyond overexpression","pmids":["28842419"],"is_preprint":false},{"year":2009,"finding":"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).","method":"In ovo electroporation (overexpression/knockdown), anterograde labeling of retinal axons","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined axonal phenotypes; single lab","pmids":["18280178"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro cochlear explant culture with anti-RGMa blocking antibody, synapse quantification (confocal microscopy), morphometric analysis of fiber branching","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined functional readout (synapse formation, axon pruning) with antibody loss-of-function; single lab","pmids":["24123853"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with gain/loss-of-function and pharmacological modulation at multiple nodes; single lab","pmids":["35664003"],"is_preprint":false}],"current_model":"RGMa is a GPI-anchored glycoprotein that functions primarily through its cell-surface receptor neogenin: it mediates axon repulsion and growth cone collapse via a neogenin–RhoA–ROCK–PKC pathway (with downstream inactivation of Ras/Akt via FAK dephosphorylation and p120GAP), undergoes autocatalytic and proprotein-convertase (Furin/SKI-1)-mediated cleavage to generate multiple membrane-bound and soluble fragments with distinct signaling outputs (C-RGMa via LARG/Rho; N-RGMa via γ-secretase/NeICD/LMO4), acts as a BMP co-receptor (binding BMP-2/4 and recruiting BMP type I receptors to enhance Smad1/5/8 signaling with altered type II receptor utilization), regulates neural tube closure, neuronal survival (acting as a neogenin ligand that suppresses neogenin's pro-apoptotic dependence-receptor activity), immune cell behavior (activating Rap1 in T cells to promote ICAM-1 adhesion; regulating macrophage CXCL2 to drive neutrophil recruitment; modulating dendritic cell maturation), and glial scar formation (by forming a complex with ALK5/Smad2/3 to potentiate TGFβ1 signaling); a ternary NEO1–NET1–RGMa super-complex additionally provides a structural mechanism for signal silencing when Netrin-1 and RGMa simultaneously occupy NEO1."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12353034"],"confidence":"High","gaps":["Receptor unidentified at this stage","Intracellular signaling not addressed","Specificity for temporal axons mechanistically unexplained"]},{"year":2004,"claim":"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","pmids":["15258591"],"confidence":"High","gaps":["Downstream death effectors not fully mapped","Link between guidance and survival outputs unclear"]},{"year":2004,"claim":"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","pmids":["14749425","15084667"],"confidence":"High","gaps":["Cellular mechanism of neural tube closure defect not resolved here","Functional role of distinct cleavage products unknown"]},{"year":2005,"claim":"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","pmids":["15975920"],"confidence":"High","gaps":["In vivo relevance of BMP co-receptor role not established","Relationship to neogenin signaling unclear"]},{"year":2007,"claim":"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","pmids":["17389603","17472960"],"confidence":"High","gaps":["GEF linking neogenin to RhoA not identified","Physiological switch between BMP and repulsive modes unclear"]},{"year":2009,"claim":"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","pmids":["19458235"],"confidence":"High","gaps":["Temporal coordination with RhoA arm not resolved","Direct neogenin–FAK link not defined"]},{"year":2011,"claim":"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","pmids":["21957482","21423182","21467223"],"confidence":"High","gaps":["Distinct downstream effectors in immune vs neuronal cells not unified","Context determining pro- vs anti-inflammatory output unclear"]},{"year":2012,"claim":"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","pmids":["22340500","22215618"],"confidence":"High","gaps":["Why multiple fragments with overlapping binding exist unresolved","Regulation of cleavage in vivo unknown"]},{"year":2013,"claim":"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","pmids":["23744777"],"confidence":"High","gaps":["Direct RGMa (vs RGMB) structure inferred by conservation","How clustering converts to intracellular signal not shown"]},{"year":2015,"claim":"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","pmids":["26292756"],"confidence":"High","gaps":["How fragment ratio is set in vivo unknown","Nuclear LMO4 transcriptional targets not defined"]},{"year":2018,"claim":"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","pmids":["29396549"],"confidence":"High","gaps":["Whether complex requires neogenin not addressed","Direct vs indirect ALK5 association unresolved"]},{"year":2021,"claim":"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","pmids":["33740419"],"confidence":"High","gaps":["In vivo prevalence of super-complex unknown","Regulation of relative ligand concentrations unclear"]},{"year":2022,"claim":"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","pmids":["35167145","36089003","35664003"],"confidence":"Medium","gaps":["Each mechanism shown by single lab","Receptor identity in non-neuronal contexts variably defined"]},{"year":2023,"claim":"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","pmids":["37992159"],"confidence":"Medium","gaps":["Single lab","Receptor mediating actin effect not defined","Mechanistic link to RhoA pathway unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,5,28,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,11]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,2,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,18,19,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,24]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,28,5,31]}],"complexes":["RGMa–neogenin (NEO1) complex","NEO1–NET1–RGM ternary super-complex","RGMa–BMP type I receptor complex","RGMa–ALK5–Smad2/3 complex"],"partners":["NEO1","BMP2","BMP4","NET1","ALK5","APP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96B86","full_name":"Repulsive guidance molecule A","aliases":["RGM domain family member A"],"length_aa":450,"mass_kda":49.4,"function":"Member of the repulsive guidance molecule (RGM) family that performs several functions in the developing and adult nervous system. Regulates cephalic neural tube closure, inhibits neurite outgrowth and cortical neuron branching, and the formation of mature synapses. Binding to its receptor NEO1/neogenin induces activation of RHOA-ROCK1/Rho-kinase signaling pathway through UNC5B-ARHGEF12/LARG-PTK2/FAK1 cascade, leading to collapse of the neuronal growth cone and neurite outgrowth inhibition. Furthermore, RGMA binding to NEO1/neogenin leads to HRAS inactivation by influencing HRAS-PTK2/FAK1-AKT1 pathway. It also functions as a bone morphogenetic protein (BMP) coreceptor that may signal through SMAD1, SMAD5, and SMAD8","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96B86/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RGMA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RGMA","total_profiled":1310},"omim":[{"mim_id":"612687","title":"RGM DOMAIN FAMILY, MEMBER B; RGMB","url":"https://www.omim.org/entry/612687"},{"mim_id":"608504","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 15; ARHGEF15","url":"https://www.omim.org/entry/608504"},{"mim_id":"607362","title":"RGM DOMAIN FAMILY, MEMBER A; RGMA","url":"https://www.omim.org/entry/607362"},{"mim_id":"601907","title":"NEOGENIN; NEO1","url":"https://www.omim.org/entry/601907"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":189.3}],"url":"https://www.proteinatlas.org/search/RGMA"},"hgnc":{"alias_symbol":["RGM"],"prev_symbol":[]},"alphafold":{"accession":"Q96B86","domains":[{"cath_id":"3.40.1000.10","chopping":"144-318","consensus_level":"high","plddt":91.3857,"start":144,"end":318},{"cath_id":"1.20.58","chopping":"50-114","consensus_level":"high","plddt":86.1502,"start":50,"end":114}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B86","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B86-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B86-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RGMA","jax_strain_url":"https://www.jax.org/strain/search?query=RGMA"},"sequence":{"accession":"Q96B86","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96B86.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96B86/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B86"}},"corpus_meta":[{"pmid":"12353034","id":"PMC_12353034","title":"RGM is a repulsive guidance molecule for retinal axons.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12353034","citation_count":250,"is_preprint":false},{"pmid":"16585268","id":"PMC_16585268","title":"RGMa inhibition promotes axonal growth and recovery after spinal cord injury.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16585268","citation_count":242,"is_preprint":false},{"pmid":"15258591","id":"PMC_15258591","title":"RGM and its receptor neogenin regulate neuronal survival.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15258591","citation_count":224,"is_preprint":false},{"pmid":"15975920","id":"PMC_15975920","title":"Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15975920","citation_count":158,"is_preprint":false},{"pmid":"14749425","id":"PMC_14749425","title":"Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/14749425","citation_count":158,"is_preprint":false},{"pmid":"21423182","id":"PMC_21423182","title":"RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21423182","citation_count":103,"is_preprint":false},{"pmid":"16836993","id":"PMC_16836993","title":"Neogenin interacts with RGMa and netrin-1 to guide axons within the embryonic vertebrate forebrain.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16836993","citation_count":102,"is_preprint":false},{"pmid":"29396549","id":"PMC_29396549","title":"RGMa mediates reactive astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29396549","citation_count":101,"is_preprint":false},{"pmid":"19897400","id":"PMC_19897400","title":"The RGM/DRAGON family of BMP co-receptors.","date":"2009","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19897400","citation_count":92,"is_preprint":false},{"pmid":"15845084","id":"PMC_15845084","title":"Spinal cord injury-induced lesional expression of the repulsive guidance molecule (RGM).","date":"2005","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15845084","citation_count":92,"is_preprint":false},{"pmid":"21957482","id":"PMC_21957482","title":"Activated microglia inhibit axonal growth through RGMa.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21957482","citation_count":89,"is_preprint":false},{"pmid":"17472960","id":"PMC_17472960","title":"Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17472960","citation_count":89,"is_preprint":false},{"pmid":"17389603","id":"PMC_17389603","title":"Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17389603","citation_count":84,"is_preprint":false},{"pmid":"14678836","id":"PMC_14678836","title":"Isolation and expression pattern of three mouse homologues of chick Rgm.","date":"2004","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/14678836","citation_count":82,"is_preprint":false},{"pmid":"15084667","id":"PMC_15084667","title":"The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15084667","citation_count":78,"is_preprint":false},{"pmid":"1824777","id":"PMC_1824777","title":"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.","date":"1991","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1824777","citation_count":73,"is_preprint":false},{"pmid":"16184425","id":"PMC_16184425","title":"Rebamipide significantly inhibits indomethacin-induced mitochondrial damage, lipid peroxidation, and apoptosis in gastric epithelial RGM-1 cells.","date":"2005","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16184425","citation_count":71,"is_preprint":false},{"pmid":"15053976","id":"PMC_15053976","title":"Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development.","date":"2004","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/15053976","citation_count":68,"is_preprint":false},{"pmid":"28874746","id":"PMC_28874746","title":"RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28874746","citation_count":68,"is_preprint":false},{"pmid":"1370226","id":"PMC_1370226","title":"Haemopoietic cell kinetics in humans treated with rGM-CSF.","date":"1992","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1370226","citation_count":65,"is_preprint":false},{"pmid":"21467223","id":"PMC_21467223","title":"Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21467223","citation_count":59,"is_preprint":false},{"pmid":"2783247","id":"PMC_2783247","title":"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.","date":"1989","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/2783247","citation_count":59,"is_preprint":false},{"pmid":"20072140","id":"PMC_20072140","title":"RGMA and IL21R show association with experimental inflammation and multiple sclerosis.","date":"2010","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20072140","citation_count":57,"is_preprint":false},{"pmid":"23744777","id":"PMC_23744777","title":"Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23744777","citation_count":55,"is_preprint":false},{"pmid":"22340500","id":"PMC_22340500","title":"SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22340500","citation_count":52,"is_preprint":false},{"pmid":"23029472","id":"PMC_23029472","title":"Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs).","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23029472","citation_count":51,"is_preprint":false},{"pmid":"3496234","id":"PMC_3496234","title":"Patterns of acute myeloid leukemia colony growth in response to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF).","date":"1987","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/3496234","citation_count":47,"is_preprint":false},{"pmid":"25482565","id":"PMC_25482565","title":"RGM regulates BMP-mediated secondary axis formation in the sea anemone Nematostella vectensis.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25482565","citation_count":46,"is_preprint":false},{"pmid":"19303019","id":"PMC_19303019","title":"Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms.","date":"2009","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19303019","citation_count":45,"is_preprint":false},{"pmid":"19036958","id":"PMC_19036958","title":"Neogenin and RGMa control neural tube closure and neuroepithelial morphology by regulating cell polarity.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19036958","citation_count":44,"is_preprint":false},{"pmid":"19458235","id":"PMC_19458235","title":"Inactivation of Ras by p120GAP via focal adhesion kinase dephosphorylation mediates RGMa-induced growth cone collapse.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19458235","citation_count":44,"is_preprint":false},{"pmid":"17615080","id":"PMC_17615080","title":"Role of RGM coreceptors in bone morphogenetic protein signaling.","date":"2007","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/17615080","citation_count":43,"is_preprint":false},{"pmid":"30798120","id":"PMC_30798120","title":"Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30798120","citation_count":41,"is_preprint":false},{"pmid":"18034283","id":"PMC_18034283","title":"Neoplastic transformation and induction of H+,K+ -adenosine triphosphatase by N-methyl-N'-nitro-N-nitrosoguanidine in the gastric epithelial RGM-1 cell line.","date":"2007","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/18034283","citation_count":41,"is_preprint":false},{"pmid":"33740419","id":"PMC_33740419","title":"Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33740419","citation_count":38,"is_preprint":false},{"pmid":"20534671","id":"PMC_20534671","title":"The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway in Caenorhabditis elegans.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20534671","citation_count":38,"is_preprint":false},{"pmid":"19268666","id":"PMC_19268666","title":"Expression of the repulsive guidance molecule RGM and its receptor neogenin after spinal cord injury in sea lamprey.","date":"2009","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19268666","citation_count":36,"is_preprint":false},{"pmid":"29259705","id":"PMC_29259705","title":"The roles of RGMa-neogenin signaling in inflammation and angiogenesis.","date":"2017","source":"Inflammation and regeneration","url":"https://pubmed.ncbi.nlm.nih.gov/29259705","citation_count":34,"is_preprint":false},{"pmid":"31899158","id":"PMC_31899158","title":"MicroRNA-4472 Promotes Tumor Proliferation and Aggressiveness in Breast Cancer by Targeting RGMA and Inducing EMT.","date":"2019","source":"Clinical breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31899158","citation_count":34,"is_preprint":false},{"pmid":"25308084","id":"PMC_25308084","title":"The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25308084","citation_count":34,"is_preprint":false},{"pmid":"1730155","id":"PMC_1730155","title":"Monocyte-derived macrophage function in HIV-infected subjects: in vitro modulation by rIFN-gamma and rGM-CSF.","date":"1992","source":"Clinical immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/1730155","citation_count":34,"is_preprint":false},{"pmid":"23389659","id":"PMC_23389659","title":"Effective neuroprotection by ischemic postconditioning is associated with a decreased expression of RGMa and inflammation mediators in ischemic rats.","date":"2013","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/23389659","citation_count":32,"is_preprint":false},{"pmid":"32590037","id":"PMC_32590037","title":"Delayed administration of the human anti-RGMa monoclonal antibody elezanumab promotes functional recovery including spontaneous voiding after spinal cord injury in rats.","date":"2020","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/32590037","citation_count":32,"is_preprint":false},{"pmid":"20457227","id":"PMC_20457227","title":"The repulsive guidance molecule, RGMa, promotes retinal ganglion cell survival in vitro and in vivo.","date":"2010","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20457227","citation_count":31,"is_preprint":false},{"pmid":"22582881","id":"PMC_22582881","title":"Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: a possible hallmark of regenerative failure in Alzheimer's disease brains.","date":"2013","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22582881","citation_count":31,"is_preprint":false},{"pmid":"32779334","id":"PMC_32779334","title":"Silencing miR-20a-5p inhibits axonal growth and neuronal branching and prevents epileptogenesis through RGMa-RhoA-mediated synaptic plasticity.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32779334","citation_count":30,"is_preprint":false},{"pmid":"23184880","id":"PMC_23184880","title":"Minocycline promotes axonal regeneration through suppression of RGMa in rat MCAO/reperfusion model.","date":"2012","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23184880","citation_count":29,"is_preprint":false},{"pmid":"24004951","id":"PMC_24004951","title":"The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans.","date":"2013","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24004951","citation_count":29,"is_preprint":false},{"pmid":"29935233","id":"PMC_29935233","title":"Adenoviral vector-induced silencing of RGMa attenuates blood-brain barrier dysfunction in a rat model of MCAO/reperfusion.","date":"2018","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/29935233","citation_count":28,"is_preprint":false},{"pmid":"28842419","id":"PMC_28842419","title":"Repulsive Guidance Molecule a (RGMa) Induces Neuropathological and Behavioral Changes That Closely Resemble Parkinson's Disease.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28842419","citation_count":28,"is_preprint":false},{"pmid":"23275173","id":"PMC_23275173","title":"CRMP-2 is involved in axon growth inhibition induced by RGMa in vitro and in vivo.","date":"2012","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23275173","citation_count":28,"is_preprint":false},{"pmid":"1377118","id":"PMC_1377118","title":"Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). A review of its pharmacological properties and prospective role in the management of myelosuppression.","date":"1992","source":"Drugs","url":"https://pubmed.ncbi.nlm.nih.gov/1377118","citation_count":25,"is_preprint":false},{"pmid":"20575069","id":"PMC_20575069","title":"Characterization of the netrin/RGMa receptor neogenin in neurogenic regions of the mouse and human adult forebrain.","date":"2010","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20575069","citation_count":25,"is_preprint":false},{"pmid":"17953666","id":"PMC_17953666","title":"RGMa inhibits neurite outgrowth of neuronal progenitors from murine enteric nervous system via the neogenin receptor in vitro.","date":"2007","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17953666","citation_count":24,"is_preprint":false},{"pmid":"31164807","id":"PMC_31164807","title":"MicroRNA-210-3p Targets RGMA to Enhance the Angiogenic Functions of Endothelial Progenitor Cells Under Hypoxic Conditions.","date":"2019","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31164807","citation_count":24,"is_preprint":false},{"pmid":"24312340","id":"PMC_24312340","title":"RGMa regulates cortical interneuron migration and differentiation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24312340","citation_count":21,"is_preprint":false},{"pmid":"34754080","id":"PMC_34754080","title":"Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34754080","citation_count":20,"is_preprint":false},{"pmid":"30487305","id":"PMC_30487305","title":"Performance of RGM Medium for Isolation of Nontuberculous Mycobacteria from Respiratory Specimens from Non-Cystic Fibrosis Patients.","date":"2019","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30487305","citation_count":20,"is_preprint":false},{"pmid":"29311561","id":"PMC_29311561","title":"Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29311561","citation_count":20,"is_preprint":false},{"pmid":"8417954","id":"PMC_8417954","title":"Modulation of macrophage Fc gamma receptors by rGM-CSF.","date":"1993","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/8417954","citation_count":20,"is_preprint":false},{"pmid":"35167145","id":"PMC_35167145","title":"RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO.","date":"2022","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35167145","citation_count":19,"is_preprint":false},{"pmid":"22215618","id":"PMC_22215618","title":"Novel roles of the chemorepellent axon guidance molecule RGMa in cell migration and adhesion.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22215618","citation_count":18,"is_preprint":false},{"pmid":"26843113","id":"PMC_26843113","title":"Lentiviral Vector-Induced Overexpression of RGMa in the Hippocampus Suppresses Seizures and Mossy Fiber Sprouting.","date":"2016","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26843113","citation_count":18,"is_preprint":false},{"pmid":"24123853","id":"PMC_24123853","title":"Inhibition of repulsive guidance molecule, RGMa, increases afferent synapse formation with auditory hair cells.","date":"2013","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/24123853","citation_count":18,"is_preprint":false},{"pmid":"17823845","id":"PMC_17823845","title":"Overexpression of repulsive guidance molecule (RGM) a induces cell death through Neogenin in early vertebrate development.","date":"2007","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/17823845","citation_count":18,"is_preprint":false},{"pmid":"18479252","id":"PMC_18479252","title":"Repulsive guidance molecule A (RGM A) and its receptor neogenin during neural and neural crest cell development of Xenopus laevis.","date":"2008","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18479252","citation_count":17,"is_preprint":false},{"pmid":"25420768","id":"PMC_25420768","title":"Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model.","date":"2014","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/25420768","citation_count":17,"is_preprint":false},{"pmid":"1707468","id":"PMC_1707468","title":"Effects of rGM-CSF and rG-CSF on the cisplatin sensitivity of the blast cells of acute myeloblastic leukemia.","date":"1991","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/1707468","citation_count":17,"is_preprint":false},{"pmid":"22568948","id":"PMC_22568948","title":"Repulsive guidance molecule A (RGMa): a molecule for all seasons.","date":"2012","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/22568948","citation_count":17,"is_preprint":false},{"pmid":"28421558","id":"PMC_28421558","title":"Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF) : A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression.","date":"1992","source":"Drugs","url":"https://pubmed.ncbi.nlm.nih.gov/28421558","citation_count":17,"is_preprint":false},{"pmid":"26292756","id":"PMC_26292756","title":"ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum.","date":"2015","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26292756","citation_count":16,"is_preprint":false},{"pmid":"35810963","id":"PMC_35810963","title":"Delayed administration of elezanumab, a human anti-RGMa neutralizing monoclonal antibody, promotes recovery following cervical spinal cord injury.","date":"2022","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/35810963","citation_count":16,"is_preprint":false},{"pmid":"19176821","id":"PMC_19176821","title":"Sustained in vivo inhibition of protein domains using single-chain Fv recombinant antibodies and its application to dissect RGMa activity on axonal outgrowth.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19176821","citation_count":15,"is_preprint":false},{"pmid":"9886182","id":"PMC_9886182","title":"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.","date":"1998","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/9886182","citation_count":15,"is_preprint":false},{"pmid":"31399534","id":"PMC_31399534","title":"Rgma-Induced Neo1 Proteolysis Promotes Neural Tube Morphogenesis.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31399534","citation_count":14,"is_preprint":false},{"pmid":"35664003","id":"PMC_35664003","title":"RGMa Participates in the Blood-Brain Barrier Dysfunction Through BMP/BMPR/YAP Signaling in Multiple Sclerosis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35664003","citation_count":14,"is_preprint":false},{"pmid":"21840379","id":"PMC_21840379","title":"Electrical stimulation of olfactory bulb downregulates RGMa expression after ischemia/reperfusion injury in rats.","date":"2011","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/21840379","citation_count":14,"is_preprint":false},{"pmid":"35789312","id":"PMC_35789312","title":"Modulation of Microglia M2 Polarization and Alleviation of Hippocampal Neuron Injury By MiR-106b-5p/RGMa in a Mouse Model of Status Epilepticus.","date":"2022","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/35789312","citation_count":14,"is_preprint":false},{"pmid":"18280178","id":"PMC_18280178","title":"Intraretinal RGMa is involved in retino-tectal mapping.","date":"2008","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/18280178","citation_count":14,"is_preprint":false},{"pmid":"24107452","id":"PMC_24107452","title":"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.","date":"2013","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24107452","citation_count":14,"is_preprint":false},{"pmid":"2645966","id":"PMC_2645966","title":"Pluripotent hemopoietic stem cells give rise to osteoclasts in vitro: effects of rGM-CSF.","date":"1989","source":"Bone and mineral","url":"https://pubmed.ncbi.nlm.nih.gov/2645966","citation_count":14,"is_preprint":false},{"pmid":"33536466","id":"PMC_33536466","title":"An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33536466","citation_count":13,"is_preprint":false},{"pmid":"38762192","id":"PMC_38762192","title":"Circular RNA circHIPK2 inhibits colon cancer cells through miR-373-3p/RGMA axis.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38762192","citation_count":12,"is_preprint":false},{"pmid":"35028889","id":"PMC_35028889","title":"Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study.","date":"2022","source":"Neurocritical care","url":"https://pubmed.ncbi.nlm.nih.gov/35028889","citation_count":12,"is_preprint":false},{"pmid":"1374343","id":"PMC_1374343","title":"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).","date":"1992","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/1374343","citation_count":12,"is_preprint":false},{"pmid":"36501143","id":"PMC_36501143","title":"C-Phycocyanin and Lycium barbarum Polysaccharides Protect against Aspirin-Induced Inflammation and Apoptosis in Gastric RGM-1 Cells.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36501143","citation_count":11,"is_preprint":false},{"pmid":"36089003","id":"PMC_36089003","title":"RGMa promotes dedifferentiation of vascular smooth muscle cells into a macrophage-like phenotype in vivo and in vitro.","date":"2022","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/36089003","citation_count":11,"is_preprint":false},{"pmid":"23073896","id":"PMC_23073896","title":"RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis.","date":"2012","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/23073896","citation_count":11,"is_preprint":false},{"pmid":"1486032","id":"PMC_1486032","title":"Effects of bryostatin 1 and rGM-CSF on the metabolism of 1-beta-D-arabinofuranosylcytosine in human leukaemic myeloblasts.","date":"1992","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/1486032","citation_count":11,"is_preprint":false},{"pmid":"1410417","id":"PMC_1410417","title":"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).","date":"1992","source":"Progress in brain research","url":"https://pubmed.ncbi.nlm.nih.gov/1410417","citation_count":11,"is_preprint":false},{"pmid":"37992159","id":"PMC_37992159","title":"RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37992159","citation_count":10,"is_preprint":false},{"pmid":"33748906","id":"PMC_33748906","title":"RGMa can induce skeletal muscle cell hyperplasia via association with neogenin signalling pathway.","date":"2021","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/33748906","citation_count":10,"is_preprint":false},{"pmid":"32948213","id":"PMC_32948213","title":"Promoting functions of microRNA-29a/199B in neurological recovery in rats with spinal cord injury through inhibition of the RGMA/STAT3 axis.","date":"2020","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/32948213","citation_count":10,"is_preprint":false},{"pmid":"35330256","id":"PMC_35330256","title":"Genomic and Experimental Analysis of the Insecticidal Factors Secreted by the Entomopathogenic Fungus Beauveria pseudobassiana RGM 2184.","date":"2022","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35330256","citation_count":10,"is_preprint":false},{"pmid":"26896667","id":"PMC_26896667","title":"A novel role for RGMa in modulation of bone marrow-derived dendritic cells maturation induced by lipopolysaccharide.","date":"2016","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26896667","citation_count":9,"is_preprint":false},{"pmid":"35255809","id":"PMC_35255809","title":"Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy.","date":"2022","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35255809","citation_count":9,"is_preprint":false},{"pmid":"33088322","id":"PMC_33088322","title":"Evaluation of soluble expression of recombinant granulocyte macrophage stimulating factor (rGM-CSF) by three different E. coli strains.","date":"2020","source":"Research in pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33088322","citation_count":9,"is_preprint":false},{"pmid":"37326791","id":"PMC_37326791","title":"Neutralizing RGMa with Elezanumab Promotes Cerebroprotection and Recovery in Rabbit Middle Cerebral Artery Occlusion.","date":"2023","source":"Translational stroke research","url":"https://pubmed.ncbi.nlm.nih.gov/37326791","citation_count":8,"is_preprint":false},{"pmid":"27545491","id":"PMC_27545491","title":"Effects of maternal lead exposure on RGMa and RGMb expression in the hippocampus and cerebral cortex of mouse pups.","date":"2016","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/27545491","citation_count":8,"is_preprint":false},{"pmid":"11731719","id":"PMC_11731719","title":"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.","date":"2002","source":"Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11731719","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50257,"output_tokens":9480,"usd":0.146485,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19548,"output_tokens":5328,"usd":0.11547,"stage2_stop_reason":"end_turn"},"total_usd":0.261955,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro growth cone collapse assay and stripe/outgrowth assay with recombinant RGMa protein\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro functional assay with recombinant protein, foundational paper, multiple assays (collapse and stripe assay)\",\n      \"pmids\": [\"12353034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In ovo gene transfer (overexpression/knockdown), immortalized neuronal cell apoptosis assay, caspase cleavage analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function in vivo, replicated in cell lines, mechanistic cleavage data, multiple orthogonal methods\",\n      \"pmids\": [\"15258591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Radiolabeled ligand binding assay, co-immunoprecipitation with BMP type I receptors, cell-based BMP signaling reporter assay, Western blot for Smad phosphorylation and Id1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay, receptor complex co-IP, downstream pathway validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"15975920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse knockout (loss-of-function genetic study), in situ hybridization for expression, biochemical characterization of processing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined morphological phenotype, replicated across multiple assays in single rigorous study\",\n      \"pmids\": [\"14749425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway (RhoA-ROCK) established in vitro, corroborated with in vivo loss-of-function antibody and defined phenotypic readout\",\n      \"pmids\": [\"16585268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"DRG cultures from neogenin-/- mice, RhoA/Rac1/Cdc42 pull-down activation assays, pharmacological inhibitors (C3-transferase, Y-27632, Gö6976), dominant-negative constructs, noggin pretreatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches (KO neurons, dominant negatives, pharmacological inhibitors, GTPase assays) in one rigorous study\",\n      \"pmids\": [\"17389603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance / radiolabeled binding assay, siRNA knockdown of individual type II receptors, BmpRII-null cell lines, BMP reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative binding data plus genetic dissection of receptor usage with multiple cell lines and siRNA, multiple orthogonal methods\",\n      \"pmids\": [\"17472960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific Western blot for FAK Tyr-397, siRNA knockdown of p120GAP, dominant-negative/constitutively active Akt expression, growth cone collapse assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and genetic approaches in a single rigorous study establishing FAK-p120GAP-Ras-Akt pathway\",\n      \"pmids\": [\"19458235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both in vitro mechanistic dissection (siRNA, antibody) and in vivo corroboration with defined phenotype\",\n      \"pmids\": [\"21957482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Rap1 activation assay (pull-down), T cell adhesion assay, RGMa siRNA knockdown in dendritic cells, adoptive transfer EAE model, neutralizing antibody treatment in vivo\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical (Rap1 pull-down, adhesion assay) and in vivo genetic/pharmacological evidence across multiple assays\",\n      \"pmids\": [\"21423182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro leukocyte migration assay, in vivo zymosan peritonitis model, neogenin knockout (gene-trap) mice, cytokine measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor dependence confirmed genetically with KO mice plus pharmacological in vitro and in vivo evidence\",\n      \"pmids\": [\"21467223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical characterization of RGMa cleavage products, furin/SKI-1 siRNA knockdown, in vivo electroporation assay for axon guidance, domain-deletion binding assays with neogenin\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical dissection of cleavage mechanism with functional in vivo validation and domain-mapping experiments\",\n      \"pmids\": [\"22340500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structural mutagenesis, functional validation of complex assembly\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation; establishes the structural basis of RGM-NEO1 signaling hub; applies to RGMA by demonstrated conservation\",\n      \"pmids\": [\"23744777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro explant migration assay, Neogenin receptor blocking, RGMa/Netrin-1 gradient co-exposure, neurite outgrowth assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays with clear mechanistic readouts (migration, outgrowth, receptor dependence), single lab\",\n      \"pmids\": [\"24312340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing complex, multiple functional readouts, in vivo and in vitro corroboration, mechanism-based rescue experiments\",\n      \"pmids\": [\"29396549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In ovo electroporation (gain/loss-of-function), dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression, in vitro axon growth assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual pathway dissection with genetic and pharmacological tools both in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"26292756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, neogenin morpholino knockdown, BMP inhibitor (noggin), in vivo morpholino knockdown of RGMa\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by deletion mutants with functional assays, neogenin dependence established, in vivo corroboration; single lab\",\n      \"pmids\": [\"22215618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown in Xenopus, axon tract analysis, double knockdown epistasis experiments\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function epistasis in Xenopus, dosage-sensitive interactions; single lab\",\n      \"pmids\": [\"16836993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown of RGMa and neogenin in Xenopus, immunofluorescence of microtubule network, neural tube morphology analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with cellular mechanistic readout (microtubule disruption), single lab\",\n      \"pmids\": [\"19036958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish morpholino knockdown, cell transplantation for cell autonomy, NeoICD overexpression rescue, immunofluorescence for microtubules and junctional complexes\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cell-autonomous function established by transplant, proteolytic mechanism with partial rescue; single lab\",\n      \"pmids\": [\"31399534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Primary cortical neuron culture with recombinant RGMa and kinase inhibitors, Western blot for pCRMP-2, adenoviral RGMa shRNA in vivo, NF-200 immunostaining\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway dissection with pharmacological inhibitors confirmed in vivo; single lab\",\n      \"pmids\": [\"23275173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure of NEO1–NET1–RGM ternary complex, cryo-EM or structural analysis of super-assembly, growth cone collapse assay, neuron migration assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of ternary and super-complex combined with functional assays demonstrating signal silencing; multiple orthogonal methods\",\n      \"pmids\": [\"33740419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic (actin depolymerization) supported by in vitro and in vivo evidence with antibody intervention; single lab\",\n      \"pmids\": [\"37992159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown, no functional validation of the RGMa-APP interaction consequence; single lab\",\n      \"pmids\": [\"22582881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic link (RGMa→CXCL2 in macrophages) corroborated in vivo with antibody intervention and defined phenotype; single lab\",\n      \"pmids\": [\"35167145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic dissection (Slug pathway) plus in vivo corroboration; single lab\",\n      \"pmids\": [\"36089003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry with cell-type markers and RhoA co-staining in rat SCI tissue sections\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization by IHC only, no direct functional manipulation; consistent with pathway placement but not mechanistically definitive\",\n      \"pmids\": [\"15845084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding kinetics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro SPR binding assay with defined Kd values; single lab but rigorous biophysical method\",\n      \"pmids\": [\"23029472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Stripe assay, explant outgrowth assay, entorhino-hippocampal coculture with neutralizing antibody and PI-PLC treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro functional assays (stripe, outgrowth, coculture) using recombinant protein and two independent loss-of-function approaches\",\n      \"pmids\": [\"15084667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Lentiviral overexpression of RGMa in rat hippocampus, behavioral seizure assessment, Timm staining for mossy fiber sprouting, electrophysiology (NMDAR current recording) in organotypic slices\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with defined phenotype plus in vitro electrophysiology; single lab\",\n      \"pmids\": [\"26843113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"AAV-mediated overexpression of RGMa in mouse midbrain, behavioral testing (motor coordination), immunohistochemistry for dopaminergic markers, microglia/astrocyte activation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in vivo with defined neurodegeneration phenotype; single lab, no mechanistic pathway placement beyond overexpression\",\n      \"pmids\": [\"28842419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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).\",\n      \"method\": \"In ovo electroporation (overexpression/knockdown), anterograde labeling of retinal axons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined axonal phenotypes; single lab\",\n      \"pmids\": [\"18280178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cochlear explant culture with anti-RGMa blocking antibody, synapse quantification (confocal microscopy), morphometric analysis of fiber branching\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined functional readout (synapse formation, axon pruning) with antibody loss-of-function; single lab\",\n      \"pmids\": [\"24123853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with gain/loss-of-function and pharmacological modulation at multiple nodes; single lab\",\n      \"pmids\": [\"35664003\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RGMa is a GPI-anchored glycoprotein that functions primarily through its cell-surface receptor neogenin: it mediates axon repulsion and growth cone collapse via a neogenin–RhoA–ROCK–PKC pathway (with downstream inactivation of Ras/Akt via FAK dephosphorylation and p120GAP), undergoes autocatalytic and proprotein-convertase (Furin/SKI-1)-mediated cleavage to generate multiple membrane-bound and soluble fragments with distinct signaling outputs (C-RGMa via LARG/Rho; N-RGMa via γ-secretase/NeICD/LMO4), acts as a BMP co-receptor (binding BMP-2/4 and recruiting BMP type I receptors to enhance Smad1/5/8 signaling with altered type II receptor utilization), regulates neural tube closure, neuronal survival (acting as a neogenin ligand that suppresses neogenin's pro-apoptotic dependence-receptor activity), immune cell behavior (activating Rap1 in T cells to promote ICAM-1 adhesion; regulating macrophage CXCL2 to drive neutrophil recruitment; modulating dendritic cell maturation), and glial scar formation (by forming a complex with ALK5/Smad2/3 to potentiate TGFβ1 signaling); a ternary NEO1–NET1–RGMa super-complex additionally provides a structural mechanism for signal silencing when Netrin-1 and RGMa simultaneously occupy NEO1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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 [#0, #5, #28]. Recombinant RGMa collapses growth cones and repels specific axon populations in vitro [#0, #28], and signals through neogenin via a RhoA\\u2013Rho kinase (ROCK)\\u2013PKC cascade that is independent of BMP signaling [#5]; downstream, RGMa\\u2013neogenin triggers FAK dephosphorylation, dissociation of p120GAP, and inactivation of Ras and Akt, while phosphorylating the cytoskeletal effector CRMP-2 to drive neurite retraction [#7, #20]. 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 \\u03b3-secretase cleavage of neogenin to liberate a nuclear intracellular domain that engages LMO4 [#11, #15]. Beyond axon guidance, RGMa acts as a dependence-receptor ligand, suppressing neogenin's caspase-mediated pro-apoptotic activity [#1], and is essential for neural tube closure, where RGMa\\u2013neogenin signaling and the proteolytically released neogenin intracellular domain drive neuroepithelial cell elongation and microtubule organization [#3, #18, #19]. 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 [#2, #6, #27]. Crystallographic studies of RGM\\u2013NEO1 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 [#12, #21]. In injury and immune contexts, RGMa is upregulated after CNS injury and by activated microglia to inhibit axon regeneration via RhoA [#4, #8], drives reactive astrogliosis and glial scar formation by complexing with the TGF\\u03b21 receptor ALK5 and Smad2/3 [#14], and modulates immune cell behavior\\u2014activating Rap1 in T cells to promote ICAM-1 adhesion, suppressing leukocyte migration through neogenin, and driving macrophage CXCL2 expression for neutrophil recruitment [#9, #10, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the founding identity of RGMa as a concentration-dependent, axon-type-specific repulsive guidance cue, defining the biological problem its mechanism must explain.\",\n      \"evidence\": \"Recombinant RGMa in growth cone collapse and stripe/outgrowth assays on retinal axons\",\n      \"pmids\": [\"12353034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor unidentified at this stage\", \"Intracellular signaling not addressed\", \"Specificity for temporal axons mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"In ovo gain/loss-of-function in chick neural tube, neuronal apoptosis and caspase cleavage assays\",\n      \"pmids\": [\"15258591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream death effectors not fully mapped\", \"Link between guidance and survival outputs unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse knockout with morphological phenotyping, in situ hybridization, biochemical processing analysis; entorhinal laminar repulsion in cocultures\",\n      \"pmids\": [\"14749425\", \"15084667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism of neural tube closure defect not resolved here\", \"Functional role of distinct cleavage products unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a second signaling modality\\u2014RGMa as a BMP co-receptor\\u2014showing its ectodomain binds BMP-2/4 and enhances Smad1/5/8 signaling, distinguishing it from the neogenin/repulsion axis.\",\n      \"evidence\": \"Radiolabeled ligand binding, co-IP with BMP type I receptors, reporter assays, Smad/Id1 Western blots\",\n      \"pmids\": [\"15975920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of BMP co-receptor role not established\", \"Relationship to neogenin signaling unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissected the repulsive signaling cascade, demonstrating RGMa\\u2013neogenin activates RhoA/ROCK/PKC independently of BMP, and quantified BMP receptor usage, separating the two RGMa pathways mechanistically.\",\n      \"evidence\": \"Neogenin-knockout DRG neurons, GTPase pull-downs, dominant-negatives, pharmacological inhibitors, noggin; SPR binding and type II receptor siRNA/null cells\",\n      \"pmids\": [\"17389603\", \"17472960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF linking neogenin to RhoA not identified\", \"Physiological switch between BMP and repulsive modes unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the repulsion pathway downstream of RhoA to FAK\\u2013p120GAP\\u2013Ras\\u2013Akt, explaining how growth cone collapse is coupled to inactivation of pro-survival/growth signaling.\",\n      \"evidence\": \"Co-IP, phospho-FAK Tyr-397 Western blot, p120GAP siRNA, constitutively active Akt, collapse assay\",\n      \"pmids\": [\"19458235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination with RhoA arm not resolved\", \"Direct neogenin\\u2013FAK link not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"21957482\", \"21423182\", \"21467223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct downstream effectors in immune vs neuronal cells not unified\", \"Context determining pro- vs anti-inflammatory output unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cleavage product characterization, furin/SKI-1 siRNA, in vivo electroporation, domain-deletion neogenin binding; Xenopus RGD/vWF domain mapping for migration vs adhesion\",\n      \"pmids\": [\"22340500\", \"22215618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why multiple fragments with overlapping binding exist unresolved\", \"Regulation of cleavage in vivo unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis of RGM\\u2013NEO1 signaling, revealing a novel RGM fold, autocatalytic cleavage mechanism, and pH-dependent conformational stabilization of paired neogenin receptors conserved across RGM family.\",\n      \"evidence\": \"X-ray crystallography of NEO1\\u2013RGMB complex with structural mutagenesis\",\n      \"pmids\": [\"23744777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RGMa (vs RGMB) structure inferred by conservation\", \"How clustering converts to intracellular signal not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how the two RGMa fragments produce distinct outputs, with C-RGMa using LARG/Rho/ROCK and N-RGMa requiring \\u03b3-secretase generation of NeICD acting via LMO4, linking proteolysis to divergent signaling.\",\n      \"evidence\": \"In ovo electroporation, dominant-negative LARG, \\u03b3-secretase inhibitor, NeICD overexpression, axon growth assays\",\n      \"pmids\": [\"26292756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fragment ratio is set in vivo unknown\", \"Nuclear LMO4 transcriptional targets not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a TGF\\u03b2 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.\",\n      \"evidence\": \"Co-IP with ALK5/Smad2/3, RGMa siRNA, TGF\\u03b21-stimulated astrocytes, rat MCAO model, p-Smad2/3 Western blots\",\n      \"pmids\": [\"29396549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether complex requires neogenin not addressed\", \"Direct vs indirect ALK5 association unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal/structural analysis of NEO1\\u2013NET1\\u2013RGM ternary and super-complex, growth cone collapse and neuron migration assays\",\n      \"pmids\": [\"33740419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo prevalence of super-complex unknown\", \"Regulation of relative ligand concentrations unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped additional context-specific RGMa functions in disease tissues\\u2014macrophage CXCL2-driven neutrophil recruitment in NMO, VSMC dedifferentiation via Slug, and BBB dysfunction via BMP2/BMPRII/YAP.\",\n      \"evidence\": \"NMO rat model with anti-RGMa antibody and macrophage assays; VSMC siRNA/overexpression and ApoE-/- carotid ligation; HBMEC overexpression/knockdown with pathway pharmacology\",\n      \"pmids\": [\"35167145\", \"36089003\", \"35664003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each mechanism shown by single lab\", \"Receptor identity in non-neuronal contexts variably defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked RGMa to actin cytoskeletal regulation in motor neurons, showing it promotes actin depolymerization to facilitate mutant SOD1 uptake, connecting RGMa to ALS pathology.\",\n      \"evidence\": \"In vitro uptake assay with anti-RGMa antibody, mSOD1 mouse histochemistry, CSF RGMa, behavioral testing\",\n      \"pmids\": [\"37992159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Receptor mediating actin effect not defined\", \"Mechanistic link to RhoA pathway unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RGMa selects among its multiple signaling modalities (neogenin repulsion, BMP co-receptor, ALK5/TGF\\u03b2 potentiation) in a given cell, and how proteolytic fragment ratios and ligand competition are regulated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5, 28, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 2, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 18, 19, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 24]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 28, 5, 31]}\n    ],\n    \"complexes\": [\"RGMa\\u2013neogenin (NEO1) complex\", \"NEO1\\u2013NET1\\u2013RGM ternary super-complex\", \"RGMa\\u2013BMP type I receptor complex\", \"RGMa\\u2013ALK5\\u2013Smad2/3 complex\"],\n    \"partners\": [\"NEO1\", \"BMP2\", \"BMP4\", \"NET1\", \"ALK5\", \"APP\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}