{"gene":"RGMA","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"RGMa is a membrane-associated GPI-anchored glycoprotein that acts as a repulsive guidance molecule for retinal axons; recombinant RGMa at low nanomolar concentrations induces collapse of temporal (but not nasal) growth cones and repels temporal retinal axons in vitro, demonstrating axon-specific repulsive activity.","method":"In vitro growth cone collapse assay, stripe assay with recombinant RGMa protein, retinal axon guidance assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with recombinant protein, multiple orthogonal functional assays, foundational paper >250 citations","pmids":["12353034"],"is_preprint":false},{"year":2004,"finding":"RGMa signals through the transmembrane receptor neogenin to mediate repulsive axon guidance. Neogenin overexpression or RGMa downregulation in the chick neural tube induces apoptosis; neogenin functions as a dependence receptor that induces cell death in the absence of RGMa, while RGMa binding to neogenin inhibits this pro-apoptotic activity. Neogenin pro-apoptotic activity is associated with caspase-mediated cleavage of its cytoplasmic domain.","method":"In ovo gene transfer (overexpression and knockdown), immortalized neuronal cell apoptosis assays, caspase cleavage assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo and in vitro methods, >200 citations, replicated concept","pmids":["15258591"],"is_preprint":false},{"year":2004,"finding":"RGMa is required for cephalic neural tube closure in mice, establishing an in vivo developmental role; mRGMa exhibits proteolytic processing and differential GPI-anchor-dependent cell-surface targeting. mRGMa is not required for anteroposterior topographic mapping of retinal ganglion cell axons to the superior colliculus.","method":"Mouse knockout (loss-of-function), in situ hybridization, biochemical processing analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined phenotypic readout, replicated in multiple homologs","pmids":["14749425"],"is_preprint":false},{"year":2004,"finding":"RGMa acts as a repulsive signal in the developing dentate gyrus: it is expressed in the inner molecular layer and repels entorhinal axons, restricting them to the outer molecular layer. Neutralizing RGMa antibody or GPI anchor digestion with phosphatidylinositol-specific phospholipase C disrupts laminar termination of the perforant pathway in entorhino-hippocampal cocultures.","method":"Stripe assay, explant outgrowth assay, entorhino-hippocampal cocultures with neutralizing antibody and enzymatic GPI anchor removal","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro methods with specific pharmacological and antibody interventions","pmids":["15084667"],"is_preprint":false},{"year":2005,"finding":"RGMa functions as a BMP co-receptor: the extracellular domain of RGMa directly binds BMP-2 and BMP-4 (but not TGF-β), forms a complex with BMP type I receptors, enhances BMP (but not TGF-β) signaling through the Smad1/5/8 pathway, and upregulates endogenous Id1 protein in cell culture.","method":"Radiolabeled BMP binding assay, co-immunoprecipitation with BMP type I receptors, Smad phosphorylation assay, Id1 western blot, cell-based reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay plus co-IP plus downstream signaling readouts, >150 citations","pmids":["15975920"],"is_preprint":false},{"year":2006,"finding":"RGMa inhibits CNS neurite outgrowth through a mechanism dependent on activation of the RhoA–Rho kinase pathway. RGMa expression is induced in oligodendrocytes, myelinated fibers, and neurons around the injury site after spinal cord injury; neutralizing antibody to RGMa promotes axonal growth of the corticospinal tract and functional recovery after thoracic hemisection.","method":"In vitro neurite outgrowth assay with RhoA pathway inhibitors, in vivo intrathecal antibody administration, axon tracing, behavioral testing","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway identified in vitro corroborated by in vivo intervention, >240 citations","pmids":["16585268"],"is_preprint":false},{"year":2007,"finding":"RGMa-induced growth cone collapse via neogenin is mediated by activation of RhoA, Rho kinase (ROCK), and PKC, but is independent of BMP signaling. Neogenin-knockout DRG neurons show no RGMa-mediated growth cone collapse or RhoA activation; dominant-negative RhoA abolishes collapse whereas dominant-negative Rac1 does not. Netrin-1 reduces RGMa-mediated collapse.","method":"DRG neuron growth cone collapse assay, neogenin-/- mouse neurons, dominant-negative constructs, Rho GTPase inhibitor C3-transferase, Y-27632, Gö6976 pharmacological inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with genetic and pharmacological tools plus multiple orthogonal pathway dissection","pmids":["17389603"],"is_preprint":false},{"year":2007,"finding":"RGMa alters BMP type II receptor utilization: in cells without RGMa, BMP2/4 signal preferentially through BMPRII; when RGMa is expressed, ActRIIA is also utilized. In BMPRII-null cells, RGMa-mediated BMP signaling requires ActRIIA. RGMa bound radiolabeled BMP2 and BMP4 with Kd ~2.4 and ~1.4 nM respectively.","method":"Radiolabeled BMP binding assay (Kd determination), siRNA knockdown of individual type II receptors, BMP signaling reporter assays in BMPRII-null cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — quantitative binding assay plus genetic receptor-swap experiments in null cell lines","pmids":["17472960"],"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 neuroepithelial cells, impairing radial intercalation, and also disrupts apicobasal polarity of the pseudostratified neuroepithelium. Neogenin and RGMa work in the same pathway to regulate cell polarity during neurulation.","method":"Morpholino knockdown in Xenopus, microtubule immunostaining, neural tube morphology analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean morpholino KD with defined cellular/structural phenotypic readout in vivo","pmids":["19036958"],"is_preprint":false},{"year":2009,"finding":"RGMa binding to neogenin leads to inactivation of Ras via the GTPase-activating protein p120GAP. FAK phosphorylated at Tyr-397 normally sequesters p120GAP via its SH2 domain; RGMa stimulation causes FAK dephosphorylation at Tyr-397, releasing p120GAP to inactivate GTP-Ras. This leads to Akt inactivation; constitutively active Akt prevents RGMa-induced growth cone collapse. Knockdown of p120GAP blocks RGMa-induced collapse.","method":"Co-immunoprecipitation (FAK–p120GAP), RhoA/Rac/Cdc42 activity assays, siRNA knockdown, dominant-negative and constitutively active Akt constructs, growth cone collapse assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic co-IP plus pathway epistasis via dominant-negative/constitutively active constructs and siRNA","pmids":["19458235"],"is_preprint":false},{"year":2011,"finding":"Activated microglia upregulate RGMa expression following LPS stimulation and inhibit axonal growth and induce growth cone collapse through direct contact in a RGMa-dependent manner; RGMa-neutralizing antibodies or siRNA knockdown attenuates microglial inhibition of neurite outgrowth. In vivo, minocycline reduces microglial activation, decreases RGMa expression, and reduces corticospinal tract dieback after SCI.","method":"Microglia-neuron co-culture with direct contact, RGMa siRNA and neutralizing antibody, in vivo SCI mouse model with minocycline treatment, axon tracing","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro and in vivo orthogonal approaches with specific RGMa knockdown","pmids":["21957482"],"is_preprint":false},{"year":2011,"finding":"RGMa expressed on dendritic cells binds to neogenin on CD4+ T cells, activating small GTPase Rap1 and increasing T cell adhesion to ICAM-1. Neutralizing anti-RGMa antibodies attenuate EAE clinical symptoms and reduce CNS inflammatory cell invasion, and reduce T cell proliferation and pro-inflammatory cytokine (IFN-γ, IL-2, IL-4, IL-17) secretion.","method":"Co-culture binding assay (RGMa-expressing BMDCs and neogenin+ T cells), Rap1 activation assay, ICAM-1 adhesion assay, in vivo EAE model with antibody blockade, adoptive transfer experiments","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — receptor-ligand binding on primary cells, downstream GTPase assay, in vivo epistasis via adoptive transfer","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 application of RGMa attenuates pro-inflammatory cytokine production and inflammatory cell infiltration in a peritonitis model. The anti-inflammatory effect of RGMa is absent in neogenin-mutant mice, establishing neogenin dependence.","method":"In vitro leukocyte migration assays, in vivo zymosan-A peritonitis model, neogenin gene-trap mutant mice","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — neogenin genetic epistasis in vivo plus pharmacological intervention","pmids":["21467223"],"is_preprint":false},{"year":2012,"finding":"RGMa is proteolytically processed by the proprotein convertases Furin and SKI-1, combined with autocatalytic cleavage and a disulfide bridge, generating four membrane-bound and three soluble forms. Both N- and C-terminal RGMa fragments bind the same fibronectin-like domains of neogenin and block neurite outgrowth; Furin/SKI-1 cleavage is essential for neogenin-mediated outgrowth inhibition in vivo.","method":"Mass spectrometry to identify fragments, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants, neogenin domain binding assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical cleavage mapping plus in vivo functional validation with multiple orthogonal methods","pmids":["22340500"],"is_preprint":false},{"year":2012,"finding":"RGMa promotes cell migration and cell adhesion outside the nervous system in a neogenin-dependent, BMP-independent manner. The RGD motif of RGMa is required for cell migration, while the partial von Willebrand factor type D (vWF) domain is preferentially required for cell adhesion. Disruption of RGMa homeostasis in vivo causes major migration defects during Xenopus gastrulation.","method":"Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, morpholino knockdown and overexpression in vivo, neogenin dependence tests","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain-mapping with deletion mutants plus in vivo phenotypic confirmation","pmids":["22215618"],"is_preprint":false},{"year":2012,"finding":"RGMa inhibits axon growth by inducing phosphorylation of CRMP-2 via both Rho-kinase and GSK-3β signaling pathways; inhibitors of either kinase reverse RGMa-induced CRMP-2 phosphorylation and neurite retraction. In vivo knockdown of RGMa after MCAO/reperfusion reduces pCRMP-2 levels and improves axonal integrity.","method":"Primary cortical neuron neurite outgrowth assay with recombinant RGMa and kinase inhibitors (Y-27632, GSK-3β inhibitor), western blot for pCRMP-2, in vivo adenoviral RGMa knockdown in rat MCAO model","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 — pharmacological pathway dissection in vitro corroborated by in vivo RNAi intervention","pmids":["23275173"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the NEO1 RGM-binding region and its complex with RGMB reveal a previously unknown protein fold for RGM and an autocatalytic cleavage mechanism. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner; this architecture is shared by all RGM–NEO1 complexes.","method":"X-ray crystallography of NEO1–RGMB complex, functional validation of autocatalytic cleavage, binding assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation, identifies core signaling hub architecture","pmids":["23744777"],"is_preprint":false},{"year":2013,"finding":"RGMa accumulates on amyloid plaques in Alzheimer's disease brains. TGFβ1, Aβ1-40, and Aβ1-42 markedly upregulate RGMa expression in human astrocytes. Co-immunoprecipitation confirmed molecular interaction between RGMa and the C-terminal fragment β of amyloid precursor protein (APP). Recombinant RGMa protein binds amyloid plaques in situ.","method":"Co-immunoprecipitation (RGMa–APP CTFβ), in situ plaque binding assay with recombinant protein, astrocyte stimulation with cytokines and Aβ peptides, immunohistochemistry","journal":"Neuropathology and applied neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP interaction with some functional context but limited mechanistic follow-up","pmids":["22582881"],"is_preprint":false},{"year":2015,"finding":"C-RGMa and N-RGMa fragments activate two distinct intracellular pathways: C-RGMa uses LARG/Rho/Rock to inhibit axonal growth, whereas N-RGMa relies on γ-secretase cleavage of the neogenin intracellular domain to generate NeICD, which uses LMO4 to block growth. In the developing tectum, C-RGMa/LARG-PDZ and N-RGMa/NeICD overexpression produce distinct layer-specific axon targeting errors.","method":"In ovo electroporation of C- and N-RGMa constructs and dominant-negative LARG (LARG-PDZ), γ-secretase inhibitor treatment, NeICD overexpression, anterograde axon labeling in chick tectum","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — dissection of two parallel pathways using genetic dominant-negatives and pharmacological inhibition in vivo","pmids":["26292756"],"is_preprint":false},{"year":2018,"finding":"RGMa promotes reactive astrogliosis and glial scar formation after stroke by forming a complex with TGFβ receptor ALK5 and Smad2/3; RGMa knockdown abrogates TGFβ1-induced ALK5–Smad2/3 interaction and subsequent Smad2/3 phosphorylation, blocking key steps of reactive astrogliosis including cellular hypertrophy, GFAP upregulation, migration, and CSPG secretion. TGFβ1 stimulates RGMa expression via ALK5.","method":"Co-immunoprecipitation (RGMa–ALK5–Smad2/3 complex), Smad2/3 phosphorylation assay, RGMa siRNA knockdown in primary astrocytes, in vivo rat MCAO model with RGMa genetic/pharmacologic inhibition","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — co-IP of ternary complex plus functional knockdown with multiple cellular readouts in vitro and in vivo","pmids":["29396549"],"is_preprint":false},{"year":2019,"finding":"RGMa-induced NEO1 glycosylation and intramembrane proteolysis generates a transient nuclear intracellular fragment (NeoICD); this proteolytic cleavage is essential for neurulation (NEC elongation) as partial rescue of Neo1a and Rgma knockdown embryos by NeoICD overexpression was demonstrated. Rgma/Neo1 signaling promotes microtubule-mediated neuroepithelial cell elongation cell-autonomously.","method":"Morpholino knockdown in zebrafish, cell transplantation, NeoICD overexpression rescue, microtubule immunostaining, glycosylation assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with rescue experiment identifies proteolytic cleavage as key signaling event","pmids":["31399534"],"is_preprint":false},{"year":2021,"finding":"Simultaneous binding of NET1 and RGMa to NEO1 forms a ternary NEO1-NET1-RGM complex that assembles into a 'trimer-of-trimers' super-assembly in the cell membrane, resulting in reciprocal silencing of both RGMa–NEO1-mediated repulsion (growth cone collapse) and NET1–NEO1-mediated attraction (neuron migration) by preventing signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering.","method":"Cryo-EM/X-ray structures of ternary NEO1-NET1-RGM complex, cell-based growth cone collapse assay, neuron migration assay, structure-guided mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — structural determination with functional validation in multiple assays; mechanistically novel","pmids":["33740419"],"is_preprint":false},{"year":2022,"finding":"RGMa signaling via neogenin on infiltrating macrophages directly regulates CXCL2 (a neutrophil chemoattractant) expression; RGMa-expressing neurons and astrocytes present ligand to neogenin-expressing macrophages in NMO lesions, driving neutrophil recruitment and astrocytopathy. Anti-RGMa antibody suppresses this pathway, reduces neutrophil infiltration, and ameliorates neuropathic pain.","method":"In vitro macrophage RGMa stimulation assay (CXCL2 measurement), NMO rat model with anti-RGMa mAb, immunohistochemistry, gene expression assays","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — direct in vitro mechanistic assay combined with in vivo model, identifies a specific downstream effector (CXCL2)","pmids":["35167145"],"is_preprint":false},{"year":2022,"finding":"RGMa causes blood-brain barrier dysfunction in endothelial cells through BMP2/BMPRII/YAP signaling: RGMa overexpression in HBMECs increases BMPRII and decreases YAP, ZO-1, and claudin-5; inhibiting BMPRII or activating YAP on an RGMa knockdown background restores tight junction proteins, confirming the pathway order.","method":"Lentiviral RGMa overexpression and knockdown in HBMECs, permeability assays, western blot for ZO-1/claudin-5/YAP/BMPRII, EAE mouse model, pharmacological BMPRII inhibition and YAP activation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain/loss with pathway epistasis, but single lab study","pmids":["35664003"],"is_preprint":false},{"year":2023,"finding":"RGMa promotes collapse of the neuronal actin barrier, facilitating cellular uptake of misfolded mutant SOD1 protein; anti-RGMa antibody inhibits actin depolymerization in motor neurons, reduces mutant SOD1 accumulation, and ameliorates clinical symptoms in mSOD1 ALS mice. RGMa concentration is elevated in CSF of ALS patients and mSOD1 mice.","method":"In vitro actin depolymerization assay, mutant SOD1 uptake assay with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model treatment, immunohistochemistry for SOD1 aggregates","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — mechanistic in vitro assay plus in vivo validation in genetic disease model, identifies novel actin barrier mechanism","pmids":["37992159"],"is_preprint":false},{"year":2009,"finding":"RGMa interacts with neogenin to mediate axon guidance in the embryonic vertebrate forebrain; dosage-sensitive genetic interactions between neogenin, RGMa, and Netrin-1 in Xenopus demonstrate they act in the same pathway to guide dorsoventral brain axons.","method":"Morpholino loss-of-function in Xenopus, double/triple partial knockdowns (genetic epistasis), axon pathway analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — dosage-sensitive epistasis in vivo, single organism/lab","pmids":["16836993"],"is_preprint":false},{"year":2009,"finding":"Intraretinal RGMa expression on retinal ganglion cell axons is required for retino-tectal topographic mapping; overexpression or knockdown of RGMa in the eye using in ovo electroporation produces terminal zone abnormalities, premature arborization stalling, overshooting, aberrant axonal turns, and intraretinal pathfinding errors.","method":"In ovo electroporation (overexpression and RNAi knockdown), anterograde axon tracing in chick optic tectum, new RGMa monoclonal antibody characterization","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function in vivo with specific phenotypic readout","pmids":["18280178"],"is_preprint":false},{"year":2012,"finding":"Surface plasmon resonance quantification reveals RGM family members exhibit differential binding kinetics for BMP ligands: RGMA has the lowest binding affinity for most BMPs tested (Kd ~14–83 nM for BMP4/BMP2), while none of the RGMs bind BMP9. RGMs preferentially bind BMP4 > BMP2 > BMP5/6/7.","method":"Surface plasmon resonance (quantitative binding kinetics)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — quantitative biophysical binding assay with rigorous controls across all family members","pmids":["23029472"],"is_preprint":false},{"year":2017,"finding":"Adeno-associated virus-mediated overexpression of RGMa in adult mouse midbrain dopaminergic neurons induces selective degeneration of substantia nigra dopaminergic neurons with microglia and astrocyte activation, accompanied by progressive movement disorder, establishing a causal role for RGMa dysregulation in dopaminergic neuron degeneration resembling Parkinson's disease.","method":"AAV-mediated targeted overexpression of RGMa in mouse substantia nigra neurons, behavioral testing (motor coordination), immunohistochemistry for DA neuron markers and glial activation, nigrostriatal integrity analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — targeted in vivo gain-of-function with defined cellular degeneration phenotype","pmids":["28842419"],"is_preprint":false},{"year":2022,"finding":"RGMa promotes dedifferentiation of contractile vascular smooth muscle cells into a macrophage-like phenotype by enhancing the function of transcription factor Slug; Slug knockdown reverses RGMa-overexpression-induced VSMC dedifferentiation. RGMa knockdown in vivo reduces neointima formation in ligated carotid arteries in ApoE-/- mice.","method":"RGMa siRNA knockdown and overexpression in ox-LDL-treated VSMCs, Slug siRNA rescue experiment, in vivo carotid artery ligation in ApoE-/- mice with RGMa knockdown, immunohistochemistry","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via Slug rescue plus in vivo validation, single lab","pmids":["36089003"],"is_preprint":false}],"current_model":"RGMa is a GPI-anchored glycoprotein that signals primarily through its transmembrane receptor neogenin to mediate context-dependent cellular outputs: in neurons, it activates RhoA/ROCK/PKC and suppresses Ras (via FAK dephosphorylation and p120GAP) and Akt to collapse growth cones and inhibit axon regeneration, while proteolytic processing by Furin/SKI-1 and autocatalytic cleavage generates multiple soluble and membrane-bound fragments (N- and C-RGMa) that engage neogenin's fibronectin-like domain through distinct downstream pathways (LARG/Rho/Rock vs. γ-secretase/NeICD/LMO4); simultaneous binding of netrin-1 and RGMa to neogenin assembles a super-complex that silences both attractive and repulsive signals; additionally, RGMa acts as a BMP co-receptor (enhancing BMP2/4 signaling via Smad1/5/8 and expanding type II receptor utilization to ActRIIA), promotes astrogliosis via ALK5/Smad2/3 complex formation, regulates immune cell trafficking and T cell activation through neogenin/Rap1/ICAM-1, drives macrophage CXCL2 production in neuroinflammation, collapses the neuronal actin barrier to promote misfolded protein uptake in ALS, and promotes VSMC dedifferentiation via Slug."},"narrative":{"teleology":[{"year":2002,"claim":"Identifying RGMa as a GPI-anchored axon repellent established the founding molecular activity: it selectively collapses temporal retinal growth cones at nanomolar concentrations, explaining topographic map selectivity in the retinotectal system.","evidence":"Recombinant RGMa in growth cone collapse and stripe assays on chick retinal axons","pmids":["12353034"],"confidence":"High","gaps":["Receptor unknown at this point","Intracellular signaling mechanism not identified","In vivo loss-of-function not yet performed"]},{"year":2004,"claim":"Three concurrent advances identified neogenin as the RGMa receptor, demonstrated that neogenin acts as a dependence receptor whose pro-apoptotic cleavage is suppressed by RGMa, showed RGMa is essential for neural tube closure in mice, and established RGMa as a repulsive cue patterning hippocampal lamination—together defining the core receptor-ligand pair and its developmental necessity.","evidence":"Mouse RGMa knockout (neural tube defect), chick neural tube in ovo electroporation (neogenin dependence receptor), entorhino-hippocampal coculture with neutralizing antibody and PI-PLC","pmids":["15258591","14749425","15084667"],"confidence":"High","gaps":["Downstream intracellular signaling cascade still unmapped","Relationship between repulsive guidance and dependence receptor functions unclear"]},{"year":2005,"claim":"Discovery that RGMa directly binds BMP-2/4 and enhances Smad1/5/8 signaling as a BMP co-receptor revealed a second, guidance-independent signaling axis, broadening RGMa from a pure axon repellent to a multifunctional signaling hub.","evidence":"Radiolabeled BMP binding, co-IP with BMP type I receptors, Smad phosphorylation and Id1 reporter assays","pmids":["15975920"],"confidence":"High","gaps":["How BMP co-receptor and neogenin-mediated repulsive functions are segregated in the same cell unclear","Type II receptor utilization not yet addressed"]},{"year":2006,"claim":"Demonstrating that RGMa inhibits neurite outgrowth through RhoA/ROCK and that anti-RGMa antibody promotes axon regeneration and functional recovery after spinal cord injury established the therapeutic rationale for blocking RGMa in CNS injury.","evidence":"In vitro neurite outgrowth with RhoA pathway inhibitors; in vivo intrathecal anti-RGMa antibody after rat spinal cord hemisection with axon tracing and behavioral testing","pmids":["16585268"],"confidence":"High","gaps":["Full signaling cascade downstream of neogenin not resolved","Contribution of other inhibitory cues in vivo not dissected"]},{"year":2007,"claim":"Genetic and pharmacological dissection in neogenin-knockout neurons demonstrated that RGMa collapse requires neogenin→RhoA/ROCK/PKC but is independent of BMP signaling, formally separating the two RGMa signaling arms; concurrently, RGMa was shown to expand BMP type II receptor utilization to ActRIIA.","evidence":"DRG neurons from neogenin−/− mice with dominant-negative RhoA/Rac1 and pharmacological inhibitors; siRNA of type II receptors in BMPRII-null cells with radiolabeled BMP binding (Kd determination)","pmids":["17389603","17472960"],"confidence":"High","gaps":["How neogenin couples to RhoA activation molecularly unknown","Whether both pathways operate simultaneously in the same cell untested"]},{"year":2008,"claim":"Showing that RGMa–neogenin signaling regulates microtubule organization and apicobasal polarity during neural fold elevation provided the cell-biological mechanism underlying the neural tube closure defect seen in RGMa knockouts.","evidence":"Morpholino knockdown in Xenopus with microtubule immunostaining and neural tube morphology analysis","pmids":["19036958"],"confidence":"High","gaps":["Direct molecular link between neogenin and microtubule regulators not identified","Whether the same polarity mechanism operates in mammals not confirmed"]},{"year":2009,"claim":"Identification of the FAK/p120GAP/Ras/Akt cascade downstream of neogenin explained how RGMa simultaneously suppresses survival signaling and activates repulsion: RGMa triggers FAK dephosphorylation, releasing p120GAP to inactivate Ras and Akt, both required for growth cone collapse.","evidence":"Co-IP of FAK–p120GAP, Rho GTPase activity assays, p120GAP siRNA, constitutively active Akt rescue in growth cone collapse assay","pmids":["19458235"],"confidence":"High","gaps":["Phosphatase responsible for FAK Tyr-397 dephosphorylation unknown","How RhoA and Ras pathways are coordinated downstream of neogenin not resolved"]},{"year":2011,"claim":"Three studies simultaneously expanded RGMa biology into the immune system: RGMa on dendritic cells activates Rap1/ICAM-1-mediated T cell adhesion via neogenin, RGMa repels leukocyte migration in a neogenin-dependent manner, and activated microglia upregulate RGMa to inhibit axonal growth—collectively establishing RGMa–neogenin as a neuroimmune signaling axis.","evidence":"DC–T cell co-culture with Rap1 assay and EAE model (anti-RGMa antibody); leukocyte migration assay and peritonitis model in neogenin gene-trap mice; microglia–neuron co-culture with RGMa siRNA and SCI model","pmids":["21423182","21467223","21957482"],"confidence":"High","gaps":["Downstream transcriptional programs in T cells not mapped","Whether neogenin on microglia also signals back to neurons unknown"]},{"year":2012,"claim":"Biochemical mapping of RGMa proteolytic processing by Furin/SKI-1 and autocatalytic cleavage revealed that multiple fragments (N-RGMa, C-RGMa) all bind neogenin's fibronectin-like domains but engage distinct downstream effectors; separately, RGMa was shown to regulate non-neuronal cell migration via its RGD motif and adhesion via its vWF domain in a neogenin-dependent, BMP-independent manner.","evidence":"Mass spectrometry fragment identification, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants; Xenopus animal cap migration/adhesion assays with deletion mutants","pmids":["22340500","22215618"],"confidence":"High","gaps":["Stoichiometry of fragment signaling in vivo unknown","Whether specific fragments dominate in specific tissues not resolved"]},{"year":2013,"claim":"Crystal structures of the NEO1–RGMB complex revealed a novel protein fold and a pH-dependent 2:2 receptor–ligand architecture that applies to all RGM family members, providing the first atomic-resolution model for RGMa–neogenin signaling.","evidence":"X-ray crystallography of NEO1–RGMB complex with functional validation of autocatalytic cleavage","pmids":["23744777"],"confidence":"High","gaps":["Structure of RGMa specifically (not RGMB) in complex with NEO1 not determined","How conformational changes propagate to the intracellular domain unknown"]},{"year":2015,"claim":"Demonstrating that C-RGMa and N-RGMa fragments activate two distinct pathways—C-RGMa via LARG/Rho/ROCK and N-RGMa via γ-secretase/NeICD/LMO4—with each producing different layer-specific targeting errors in the tectum, resolved how a single ligand generates multiple context-dependent outputs through proteolytic diversification.","evidence":"In ovo electroporation of fragment constructs and dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression in chick tectum with anterograde tracing","pmids":["26292756"],"confidence":"High","gaps":["What determines which fragment predominates at a given synapse unknown","Whether both pathways can operate simultaneously in the same neuron untested"]},{"year":2018,"claim":"Discovery that RGMa scaffolds a TGFβ/ALK5/Smad2/3 complex in astrocytes to drive reactive gliosis after stroke revealed a third major signaling mode—distinct from both neogenin-mediated repulsion and BMP co-receptor function—linking RGMa to scar formation.","evidence":"Co-IP of RGMa–ALK5–Smad2/3 complex, RGMa siRNA blocking TGFβ1-induced Smad2/3 phosphorylation in primary astrocytes, in vivo MCAO model","pmids":["29396549"],"confidence":"High","gaps":["Whether RGMa binds ALK5 directly or through an intermediary unclear","Relative contribution of BMP vs. TGFβ arms to glial scar unknown"]},{"year":2019,"claim":"Showing that RGMa-induced neogenin glycosylation and intramembrane proteolysis generates a nuclear NeoICD fragment essential for neuroepithelial cell elongation during neurulation provided the mechanistic link between RGMa signaling and the microtubule-dependent cell shape changes underlying neural tube closure.","evidence":"Zebrafish morpholino knockdown with NeoICD overexpression rescue, cell transplantation, microtubule immunostaining","pmids":["31399534"],"confidence":"High","gaps":["Nuclear targets of NeoICD during neurulation not identified","Whether this cleavage event is regulated by specific proteases beyond γ-secretase unknown"]},{"year":2021,"claim":"Cryo-EM and X-ray structures of the ternary NEO1–NET1–RGM super-complex revealed that simultaneous ligand binding assembles a trimer-of-trimers that sterically prevents signaling-competent configurations of either pathway, explaining how netrin-1 silences RGMa repulsion and vice versa.","evidence":"Cryo-EM/X-ray crystallography of ternary complex, structure-guided mutagenesis, growth cone collapse and neuron migration assays","pmids":["33740419"],"confidence":"High","gaps":["In vivo relevance of the super-complex at guidance decision points not demonstrated","Kinetics of complex assembly/disassembly unknown"]},{"year":2022,"claim":"Three studies expanded RGMa pathobiology: RGMa on neurons/astrocytes drives macrophage CXCL2 production via neogenin to recruit neutrophils in NMO; RGMa disrupts BBB integrity through BMP2/BMPRII/YAP-mediated tight junction loss; and RGMa promotes VSMC dedifferentiation via Slug to drive neointima formation—demonstrating breadth beyond axon guidance.","evidence":"Macrophage stimulation assay and NMO rat model with anti-RGMa mAb; HBMEC RGMa overexpression/knockdown with BMPRII inhibition and YAP activation; VSMC ox-LDL model with Slug siRNA rescue and carotid ligation in ApoE−/− mice","pmids":["35167145","35664003","36089003"],"confidence":"High","gaps":["Whether CXCL2 regulation is Rap1-dependent or uses a distinct pathway unclear","BBB finding from a single lab awaits independent replication","VSMC dedifferentiation mechanism downstream of Slug not mapped"]},{"year":2023,"claim":"Demonstrating that RGMa collapses the neuronal actin barrier to promote uptake of misfolded SOD1, with anti-RGMa antibody reducing aggregation and symptoms in ALS mice, identified a novel cell-biological mechanism linking RGMa to proteinopathy spread.","evidence":"In vitro actin depolymerization and mutant SOD1 uptake assays with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model","pmids":["37992159"],"confidence":"High","gaps":["Whether actin barrier collapse is neogenin-dependent not formally tested","Whether this mechanism generalizes to other misfolded proteins (e.g. TDP-43, α-synuclein) unknown"]},{"year":null,"claim":"Key unresolved questions include: how cells coordinate the three major RGMa signaling modes (neogenin repulsion, BMP co-receptor, TGFβ/ALK5 scaffolding) in a context-dependent manner; the precise protease(s) and regulation of RGMa fragment balance in vivo; nuclear targets of NeoICD beyond LMO4; and whether the structural super-complex architecture with netrin-1 operates at in vivo guidance decision points.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model for how cells select among parallel RGMa signaling outputs","In vivo fragment-specific signaling not mapped at single-cell resolution","Therapeutic antibodies target total RGMa—fragment-selective approaches not developed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,19]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,13,14]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,13,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,7,9,18,19,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,8,20,25,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,28]}],"complexes":["NEO1-RGMa-NET1 ternary super-complex","RGMa-BMP-BMPRI co-receptor complex","RGMa-ALK5-Smad2/3 complex"],"partners":["NEO1","BMP2","BMP4","ALK5","NTN1","LARG","LMO4","SLUG"],"other_free_text":[]},"mechanistic_narrative":"RGMa is a GPI-anchored repulsive guidance molecule that signals through the transmembrane receptor neogenin to control axon guidance, neural tube closure, immune cell trafficking, and BMP pathway modulation across diverse cell types. In neurons, RGMa binding to neogenin activates RhoA/ROCK/PKC to collapse growth cones and inhibits Ras (via FAK dephosphorylation and p120GAP release) and Akt to suppress axon outgrowth; proteolytic processing by Furin/SKI-1 generates N- and C-terminal fragments that engage distinct downstream pathways—C-RGMa signals through LARG/Rho/ROCK while N-RGMa triggers γ-secretase cleavage of neogenin to produce NeICD/LMO4—and simultaneous binding of netrin-1 and RGMa to neogenin assembles a super-complex that silences both repulsive and attractive outputs [PMID:12353034, PMID:17389603, PMID:19458235, PMID:22340500, PMID:26292756, PMID:33740419]. RGMa independently functions as a BMP co-receptor that directly binds BMP-2/4, enhances Smad1/5/8 signaling, and expands type II receptor utilization to include ActRIIA, while in astrocytes it promotes reactive gliosis by scaffolding a TGFβ/ALK5/Smad2/3 complex [PMID:15975920, PMID:17472960, PMID:29396549]. In the immune system, RGMa on dendritic cells engages neogenin on T cells to activate Rap1 and ICAM-1-mediated adhesion, repels leukocyte migration, and drives macrophage CXCL2 production to recruit neutrophils in neuroinflammatory lesions; antibody blockade of RGMa ameliorates experimental autoimmune encephalomyelitis, peritonitis, and neuromyelitis optica models [PMID:21423182, PMID:21467223, PMID:35167145]."},"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 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Neogenin overexpression or RGMa downregulation in the chick neural tube induces apoptosis; neogenin functions as a dependence receptor that induces cell death in the absence of RGMa, while RGMa binding to neogenin inhibits this pro-apoptotic activity. Neogenin pro-apoptotic activity is associated with caspase-mediated cleavage of its cytoplasmic domain.\",\n      \"method\": \"In ovo gene transfer (overexpression and knockdown), immortalized neuronal cell apoptosis assays, caspase cleavage assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo and in vitro methods, >200 citations, replicated concept\",\n      \"pmids\": [\"15258591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RGMa is required for cephalic neural tube closure in mice, establishing an in vivo developmental role; mRGMa exhibits proteolytic processing and differential GPI-anchor-dependent cell-surface targeting. mRGMa is not required for anteroposterior topographic mapping of retinal ganglion cell axons to the superior colliculus.\",\n      \"method\": \"Mouse knockout (loss-of-function), in situ hybridization, biochemical processing analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotypic readout, replicated in multiple homologs\",\n      \"pmids\": [\"14749425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RGMa acts as a repulsive signal in the developing dentate gyrus: it is expressed in the inner molecular layer and repels entorhinal axons, restricting them to the outer molecular layer. Neutralizing RGMa antibody or GPI anchor digestion with phosphatidylinositol-specific phospholipase C disrupts laminar termination of the perforant pathway in entorhino-hippocampal cocultures.\",\n      \"method\": \"Stripe assay, explant outgrowth assay, entorhino-hippocampal cocultures with neutralizing antibody and enzymatic GPI anchor removal\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro methods with specific pharmacological and antibody interventions\",\n      \"pmids\": [\"15084667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RGMa functions as a BMP co-receptor: the extracellular domain of RGMa directly binds BMP-2 and BMP-4 (but not TGF-β), forms a complex with BMP type I receptors, enhances BMP (but not TGF-β) signaling through the Smad1/5/8 pathway, and upregulates endogenous Id1 protein in cell culture.\",\n      \"method\": \"Radiolabeled BMP binding assay, co-immunoprecipitation with BMP type I receptors, Smad phosphorylation assay, Id1 western blot, cell-based reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay plus co-IP plus downstream signaling readouts, >150 citations\",\n      \"pmids\": [\"15975920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RGMa inhibits CNS neurite outgrowth through a mechanism dependent on activation of the RhoA–Rho kinase pathway. RGMa expression is induced in oligodendrocytes, myelinated fibers, and neurons around the injury site after spinal cord injury; neutralizing antibody to RGMa promotes axonal growth of the corticospinal tract and functional recovery after thoracic hemisection.\",\n      \"method\": \"In vitro neurite outgrowth assay with RhoA pathway inhibitors, in vivo intrathecal antibody administration, axon tracing, behavioral testing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway identified in vitro corroborated by in vivo intervention, >240 citations\",\n      \"pmids\": [\"16585268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RGMa-induced growth cone collapse via neogenin is mediated by activation of RhoA, Rho kinase (ROCK), and PKC, but is independent of BMP signaling. Neogenin-knockout DRG neurons show no RGMa-mediated growth cone collapse or RhoA activation; dominant-negative RhoA abolishes collapse whereas dominant-negative Rac1 does not. Netrin-1 reduces RGMa-mediated collapse.\",\n      \"method\": \"DRG neuron growth cone collapse assay, neogenin-/- mouse neurons, dominant-negative constructs, Rho GTPase inhibitor C3-transferase, Y-27632, Gö6976 pharmacological inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with genetic and pharmacological tools plus multiple orthogonal pathway dissection\",\n      \"pmids\": [\"17389603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RGMa alters BMP type II receptor utilization: in cells without RGMa, BMP2/4 signal preferentially through BMPRII; when RGMa is expressed, ActRIIA is also utilized. In BMPRII-null cells, RGMa-mediated BMP signaling requires ActRIIA. RGMa bound radiolabeled BMP2 and BMP4 with Kd ~2.4 and ~1.4 nM respectively.\",\n      \"method\": \"Radiolabeled BMP binding assay (Kd determination), siRNA knockdown of individual type II receptors, BMP signaling reporter assays in BMPRII-null cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative binding assay plus genetic receptor-swap experiments in null cell lines\",\n      \"pmids\": [\"17472960\"],\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 neuroepithelial cells, impairing radial intercalation, and also disrupts apicobasal polarity of the pseudostratified neuroepithelium. Neogenin and RGMa work in the same pathway to regulate cell polarity during neurulation.\",\n      \"method\": \"Morpholino knockdown in Xenopus, microtubule immunostaining, neural tube morphology analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean morpholino KD with defined cellular/structural phenotypic readout in vivo\",\n      \"pmids\": [\"19036958\"],\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. FAK phosphorylated at Tyr-397 normally sequesters p120GAP via its SH2 domain; RGMa stimulation causes FAK dephosphorylation at Tyr-397, releasing p120GAP to inactivate GTP-Ras. This leads to Akt inactivation; constitutively active Akt prevents RGMa-induced growth cone collapse. Knockdown of p120GAP blocks RGMa-induced collapse.\",\n      \"method\": \"Co-immunoprecipitation (FAK–p120GAP), RhoA/Rac/Cdc42 activity assays, siRNA knockdown, dominant-negative and constitutively active Akt constructs, growth cone collapse assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic co-IP plus pathway epistasis via dominant-negative/constitutively active constructs and siRNA\",\n      \"pmids\": [\"19458235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Activated microglia upregulate RGMa expression following LPS stimulation and inhibit axonal growth and induce growth cone collapse through direct contact in a RGMa-dependent manner; RGMa-neutralizing antibodies or siRNA knockdown attenuates microglial inhibition of neurite outgrowth. In vivo, minocycline reduces microglial activation, decreases RGMa expression, and reduces corticospinal tract dieback after SCI.\",\n      \"method\": \"Microglia-neuron co-culture with direct contact, RGMa siRNA and neutralizing antibody, in vivo SCI mouse model with minocycline treatment, axon tracing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo orthogonal approaches with specific RGMa knockdown\",\n      \"pmids\": [\"21957482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RGMa expressed on dendritic cells binds to neogenin on CD4+ T cells, activating small GTPase Rap1 and increasing T cell adhesion to ICAM-1. Neutralizing anti-RGMa antibodies attenuate EAE clinical symptoms and reduce CNS inflammatory cell invasion, and reduce T cell proliferation and pro-inflammatory cytokine (IFN-γ, IL-2, IL-4, IL-17) secretion.\",\n      \"method\": \"Co-culture binding assay (RGMa-expressing BMDCs and neogenin+ T cells), Rap1 activation assay, ICAM-1 adhesion assay, in vivo EAE model with antibody blockade, adoptive transfer experiments\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand binding on primary cells, downstream GTPase assay, in vivo epistasis via adoptive transfer\",\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 application of RGMa attenuates pro-inflammatory cytokine production and inflammatory cell infiltration in a peritonitis model. The anti-inflammatory effect of RGMa is absent in neogenin-mutant mice, establishing neogenin dependence.\",\n      \"method\": \"In vitro leukocyte migration assays, in vivo zymosan-A peritonitis model, neogenin gene-trap mutant mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — neogenin genetic epistasis in vivo plus pharmacological intervention\",\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, combined with autocatalytic cleavage and a disulfide bridge, generating four membrane-bound and three soluble forms. Both N- and C-terminal RGMa fragments bind the same fibronectin-like domains of neogenin and block neurite outgrowth; Furin/SKI-1 cleavage is essential for neogenin-mediated outgrowth inhibition in vivo.\",\n      \"method\": \"Mass spectrometry to identify fragments, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants, neogenin domain binding assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical cleavage mapping plus in vivo functional validation with multiple orthogonal methods\",\n      \"pmids\": [\"22340500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RGMa promotes cell migration and cell adhesion outside the nervous system in a neogenin-dependent, BMP-independent manner. The RGD motif of RGMa is required for cell migration, while the partial von Willebrand factor type D (vWF) domain is preferentially required for cell adhesion. Disruption of RGMa homeostasis in vivo causes major migration defects during Xenopus gastrulation.\",\n      \"method\": \"Xenopus animal cap explant migration and adhesion assays, RGMa deletion mutants, morpholino knockdown and overexpression in vivo, neogenin dependence tests\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-mapping with deletion mutants plus in vivo phenotypic confirmation\",\n      \"pmids\": [\"22215618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RGMa inhibits axon growth by inducing phosphorylation of CRMP-2 via both Rho-kinase and GSK-3β signaling pathways; inhibitors of either kinase reverse RGMa-induced CRMP-2 phosphorylation and neurite retraction. In vivo knockdown of RGMa after MCAO/reperfusion reduces pCRMP-2 levels and improves axonal integrity.\",\n      \"method\": \"Primary cortical neuron neurite outgrowth assay with recombinant RGMa and kinase inhibitors (Y-27632, GSK-3β inhibitor), western blot for pCRMP-2, in vivo adenoviral RGMa knockdown in rat MCAO model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection in vitro corroborated by in vivo RNAi intervention\",\n      \"pmids\": [\"23275173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the NEO1 RGM-binding region and its complex with RGMB reveal a previously unknown protein fold for RGM and an autocatalytic cleavage mechanism. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner; this architecture is shared by all RGM–NEO1 complexes.\",\n      \"method\": \"X-ray crystallography of NEO1–RGMB complex, functional validation of autocatalytic cleavage, binding assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation, identifies core signaling hub architecture\",\n      \"pmids\": [\"23744777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RGMa accumulates on amyloid plaques in Alzheimer's disease brains. TGFβ1, Aβ1-40, and Aβ1-42 markedly upregulate RGMa expression in human astrocytes. Co-immunoprecipitation confirmed molecular interaction between RGMa and the C-terminal fragment β of amyloid precursor protein (APP). Recombinant RGMa protein binds amyloid plaques in situ.\",\n      \"method\": \"Co-immunoprecipitation (RGMa–APP CTFβ), in situ plaque binding assay with recombinant protein, astrocyte stimulation with cytokines and Aβ peptides, immunohistochemistry\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP interaction with some functional context but limited mechanistic follow-up\",\n      \"pmids\": [\"22582881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C-RGMa and N-RGMa fragments activate two distinct intracellular pathways: C-RGMa uses LARG/Rho/Rock to inhibit axonal growth, whereas N-RGMa relies on γ-secretase cleavage of the neogenin intracellular domain to generate NeICD, which uses LMO4 to block growth. In the developing tectum, C-RGMa/LARG-PDZ and N-RGMa/NeICD overexpression produce distinct layer-specific axon targeting errors.\",\n      \"method\": \"In ovo electroporation of C- and N-RGMa constructs and dominant-negative LARG (LARG-PDZ), γ-secretase inhibitor treatment, NeICD overexpression, anterograde axon labeling in chick tectum\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dissection of two parallel pathways using genetic dominant-negatives and pharmacological inhibition in vivo\",\n      \"pmids\": [\"26292756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RGMa promotes reactive astrogliosis and glial scar formation after stroke by forming a complex with TGFβ receptor ALK5 and Smad2/3; RGMa knockdown abrogates TGFβ1-induced ALK5–Smad2/3 interaction and subsequent Smad2/3 phosphorylation, blocking key steps of reactive astrogliosis including cellular hypertrophy, GFAP upregulation, migration, and CSPG secretion. TGFβ1 stimulates RGMa expression via ALK5.\",\n      \"method\": \"Co-immunoprecipitation (RGMa–ALK5–Smad2/3 complex), Smad2/3 phosphorylation assay, RGMa siRNA knockdown in primary astrocytes, in vivo rat MCAO model with RGMa genetic/pharmacologic inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of ternary complex plus functional knockdown with multiple cellular readouts in vitro and in vivo\",\n      \"pmids\": [\"29396549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RGMa-induced NEO1 glycosylation and intramembrane proteolysis generates a transient nuclear intracellular fragment (NeoICD); this proteolytic cleavage is essential for neurulation (NEC elongation) as partial rescue of Neo1a and Rgma knockdown embryos by NeoICD overexpression was demonstrated. Rgma/Neo1 signaling promotes microtubule-mediated neuroepithelial cell elongation cell-autonomously.\",\n      \"method\": \"Morpholino knockdown in zebrafish, cell transplantation, NeoICD overexpression rescue, microtubule immunostaining, glycosylation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with rescue experiment identifies proteolytic cleavage as key signaling event\",\n      \"pmids\": [\"31399534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Simultaneous binding of NET1 and RGMa to NEO1 forms a ternary NEO1-NET1-RGM complex that assembles into a 'trimer-of-trimers' super-assembly in the cell membrane, resulting in reciprocal silencing of both RGMa–NEO1-mediated repulsion (growth cone collapse) and NET1–NEO1-mediated attraction (neuron migration) by preventing signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering.\",\n      \"method\": \"Cryo-EM/X-ray structures of ternary NEO1-NET1-RGM complex, cell-based growth cone collapse assay, neuron migration assay, structure-guided mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination with functional validation in multiple assays; mechanistically novel\",\n      \"pmids\": [\"33740419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGMa signaling via neogenin on infiltrating macrophages directly regulates CXCL2 (a neutrophil chemoattractant) expression; RGMa-expressing neurons and astrocytes present ligand to neogenin-expressing macrophages in NMO lesions, driving neutrophil recruitment and astrocytopathy. Anti-RGMa antibody suppresses this pathway, reduces neutrophil infiltration, and ameliorates neuropathic pain.\",\n      \"method\": \"In vitro macrophage RGMa stimulation assay (CXCL2 measurement), NMO rat model with anti-RGMa mAb, immunohistochemistry, gene expression assays\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro mechanistic assay combined with in vivo model, identifies a specific downstream effector (CXCL2)\",\n      \"pmids\": [\"35167145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGMa causes blood-brain barrier dysfunction in endothelial cells through BMP2/BMPRII/YAP signaling: RGMa overexpression in HBMECs increases BMPRII and decreases YAP, ZO-1, and claudin-5; inhibiting BMPRII or activating YAP on an RGMa knockdown background restores tight junction proteins, confirming the pathway order.\",\n      \"method\": \"Lentiviral RGMa overexpression and knockdown in HBMECs, permeability assays, western blot for ZO-1/claudin-5/YAP/BMPRII, EAE mouse model, pharmacological BMPRII inhibition and YAP activation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain/loss with pathway epistasis, but single lab study\",\n      \"pmids\": [\"35664003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RGMa promotes collapse of the neuronal actin barrier, facilitating cellular uptake of misfolded mutant SOD1 protein; anti-RGMa antibody inhibits actin depolymerization in motor neurons, reduces mutant SOD1 accumulation, and ameliorates clinical symptoms in mSOD1 ALS mice. RGMa concentration is elevated in CSF of ALS patients and mSOD1 mice.\",\n      \"method\": \"In vitro actin depolymerization assay, mutant SOD1 uptake assay with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model treatment, immunohistochemistry for SOD1 aggregates\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic in vitro assay plus in vivo validation in genetic disease model, identifies novel actin barrier mechanism\",\n      \"pmids\": [\"37992159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RGMa interacts with neogenin to mediate axon guidance in the embryonic vertebrate forebrain; dosage-sensitive genetic interactions between neogenin, RGMa, and Netrin-1 in Xenopus demonstrate they act in the same pathway to guide dorsoventral brain axons.\",\n      \"method\": \"Morpholino loss-of-function in Xenopus, double/triple partial knockdowns (genetic epistasis), axon pathway analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dosage-sensitive epistasis in vivo, single organism/lab\",\n      \"pmids\": [\"16836993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Intraretinal RGMa expression on retinal ganglion cell axons is required for retino-tectal topographic mapping; overexpression or knockdown of RGMa in the eye using in ovo electroporation produces terminal zone abnormalities, premature arborization stalling, overshooting, aberrant axonal turns, and intraretinal pathfinding errors.\",\n      \"method\": \"In ovo electroporation (overexpression and RNAi knockdown), anterograde axon tracing in chick optic tectum, new RGMa monoclonal antibody characterization\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in vivo with specific phenotypic readout\",\n      \"pmids\": [\"18280178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Surface plasmon resonance quantification reveals RGM family members exhibit differential binding kinetics for BMP ligands: RGMA has the lowest binding affinity for most BMPs tested (Kd ~14–83 nM for BMP4/BMP2), while none of the RGMs bind BMP9. RGMs preferentially bind BMP4 > BMP2 > BMP5/6/7.\",\n      \"method\": \"Surface plasmon resonance (quantitative binding kinetics)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative biophysical binding assay with rigorous controls across all family members\",\n      \"pmids\": [\"23029472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adeno-associated virus-mediated overexpression of RGMa in adult mouse midbrain dopaminergic neurons induces selective degeneration of substantia nigra dopaminergic neurons with microglia and astrocyte activation, accompanied by progressive movement disorder, establishing a causal role for RGMa dysregulation in dopaminergic neuron degeneration resembling Parkinson's disease.\",\n      \"method\": \"AAV-mediated targeted overexpression of RGMa in mouse substantia nigra neurons, behavioral testing (motor coordination), immunohistochemistry for DA neuron markers and glial activation, nigrostriatal integrity analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — targeted in vivo gain-of-function with defined cellular degeneration phenotype\",\n      \"pmids\": [\"28842419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGMa promotes dedifferentiation of contractile vascular smooth muscle cells into a macrophage-like phenotype by enhancing the function of transcription factor Slug; Slug knockdown reverses RGMa-overexpression-induced VSMC dedifferentiation. RGMa knockdown in vivo reduces neointima formation in ligated carotid arteries in ApoE-/- mice.\",\n      \"method\": \"RGMa siRNA knockdown and overexpression in ox-LDL-treated VSMCs, Slug siRNA rescue experiment, in vivo carotid artery ligation in ApoE-/- mice with RGMa knockdown, immunohistochemistry\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via Slug rescue plus in vivo validation, single lab\",\n      \"pmids\": [\"36089003\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RGMa is a GPI-anchored glycoprotein that signals primarily through its transmembrane receptor neogenin to mediate context-dependent cellular outputs: in neurons, it activates RhoA/ROCK/PKC and suppresses Ras (via FAK dephosphorylation and p120GAP) and Akt to collapse growth cones and inhibit axon regeneration, while proteolytic processing by Furin/SKI-1 and autocatalytic cleavage generates multiple soluble and membrane-bound fragments (N- and C-RGMa) that engage neogenin's fibronectin-like domain through distinct downstream pathways (LARG/Rho/Rock vs. γ-secretase/NeICD/LMO4); simultaneous binding of netrin-1 and RGMa to neogenin assembles a super-complex that silences both attractive and repulsive signals; additionally, RGMa acts as a BMP co-receptor (enhancing BMP2/4 signaling via Smad1/5/8 and expanding type II receptor utilization to ActRIIA), promotes astrogliosis via ALK5/Smad2/3 complex formation, regulates immune cell trafficking and T cell activation through neogenin/Rap1/ICAM-1, drives macrophage CXCL2 production in neuroinflammation, collapses the neuronal actin barrier to promote misfolded protein uptake in ALS, and promotes VSMC dedifferentiation via Slug.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RGMa is a GPI-anchored repulsive guidance molecule that signals through the transmembrane receptor neogenin to control axon guidance, neural tube closure, immune cell trafficking, and BMP pathway modulation across diverse cell types. In neurons, RGMa binding to neogenin activates RhoA/ROCK/PKC to collapse growth cones and inhibits Ras (via FAK dephosphorylation and p120GAP release) and Akt to suppress axon outgrowth; proteolytic processing by Furin/SKI-1 generates N- and C-terminal fragments that engage distinct downstream pathways—C-RGMa signals through LARG/Rho/ROCK while N-RGMa triggers γ-secretase cleavage of neogenin to produce NeICD/LMO4—and simultaneous binding of netrin-1 and RGMa to neogenin assembles a super-complex that silences both repulsive and attractive outputs [PMID:12353034, PMID:17389603, PMID:19458235, PMID:22340500, PMID:26292756, PMID:33740419]. RGMa independently functions as a BMP co-receptor that directly binds BMP-2/4, enhances Smad1/5/8 signaling, and expands type II receptor utilization to include ActRIIA, while in astrocytes it promotes reactive gliosis by scaffolding a TGFβ/ALK5/Smad2/3 complex [PMID:15975920, PMID:17472960, PMID:29396549]. In the immune system, RGMa on dendritic cells engages neogenin on T cells to activate Rap1 and ICAM-1-mediated adhesion, repels leukocyte migration, and drives macrophage CXCL2 production to recruit neutrophils in neuroinflammatory lesions; antibody blockade of RGMa ameliorates experimental autoimmune encephalomyelitis, peritonitis, and neuromyelitis optica models [PMID:21423182, PMID:21467223, PMID:35167145].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying RGMa as a GPI-anchored axon repellent established the founding molecular activity: it selectively collapses temporal retinal growth cones at nanomolar concentrations, explaining topographic map selectivity in the retinotectal system.\",\n      \"evidence\": \"Recombinant RGMa in growth cone collapse and stripe assays on chick retinal axons\",\n      \"pmids\": [\"12353034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor unknown at this point\", \"Intracellular signaling mechanism not identified\", \"In vivo loss-of-function not yet performed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Three concurrent advances identified neogenin as the RGMa receptor, demonstrated that neogenin acts as a dependence receptor whose pro-apoptotic cleavage is suppressed by RGMa, showed RGMa is essential for neural tube closure in mice, and established RGMa as a repulsive cue patterning hippocampal lamination—together defining the core receptor-ligand pair and its developmental necessity.\",\n      \"evidence\": \"Mouse RGMa knockout (neural tube defect), chick neural tube in ovo electroporation (neogenin dependence receptor), entorhino-hippocampal coculture with neutralizing antibody and PI-PLC\",\n      \"pmids\": [\"15258591\", \"14749425\", \"15084667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intracellular signaling cascade still unmapped\", \"Relationship between repulsive guidance and dependence receptor functions unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that RGMa directly binds BMP-2/4 and enhances Smad1/5/8 signaling as a BMP co-receptor revealed a second, guidance-independent signaling axis, broadening RGMa from a pure axon repellent to a multifunctional signaling hub.\",\n      \"evidence\": \"Radiolabeled BMP binding, co-IP with BMP type I receptors, Smad phosphorylation and Id1 reporter assays\",\n      \"pmids\": [\"15975920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BMP co-receptor and neogenin-mediated repulsive functions are segregated in the same cell unclear\", \"Type II receptor utilization not yet addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that RGMa inhibits neurite outgrowth through RhoA/ROCK and that anti-RGMa antibody promotes axon regeneration and functional recovery after spinal cord injury established the therapeutic rationale for blocking RGMa in CNS injury.\",\n      \"evidence\": \"In vitro neurite outgrowth with RhoA pathway inhibitors; in vivo intrathecal anti-RGMa antibody after rat spinal cord hemisection with axon tracing and behavioral testing\",\n      \"pmids\": [\"16585268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full signaling cascade downstream of neogenin not resolved\", \"Contribution of other inhibitory cues in vivo not dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic and pharmacological dissection in neogenin-knockout neurons demonstrated that RGMa collapse requires neogenin→RhoA/ROCK/PKC but is independent of BMP signaling, formally separating the two RGMa signaling arms; concurrently, RGMa was shown to expand BMP type II receptor utilization to ActRIIA.\",\n      \"evidence\": \"DRG neurons from neogenin−/− mice with dominant-negative RhoA/Rac1 and pharmacological inhibitors; siRNA of type II receptors in BMPRII-null cells with radiolabeled BMP binding (Kd determination)\",\n      \"pmids\": [\"17389603\", \"17472960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How neogenin couples to RhoA activation molecularly unknown\", \"Whether both pathways operate simultaneously in the same cell untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that RGMa–neogenin signaling regulates microtubule organization and apicobasal polarity during neural fold elevation provided the cell-biological mechanism underlying the neural tube closure defect seen in RGMa knockouts.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus with microtubule immunostaining and neural tube morphology analysis\",\n      \"pmids\": [\"19036958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between neogenin and microtubule regulators not identified\", \"Whether the same polarity mechanism operates in mammals not confirmed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of the FAK/p120GAP/Ras/Akt cascade downstream of neogenin explained how RGMa simultaneously suppresses survival signaling and activates repulsion: RGMa triggers FAK dephosphorylation, releasing p120GAP to inactivate Ras and Akt, both required for growth cone collapse.\",\n      \"evidence\": \"Co-IP of FAK–p120GAP, Rho GTPase activity assays, p120GAP siRNA, constitutively active Akt rescue in growth cone collapse assay\",\n      \"pmids\": [\"19458235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase responsible for FAK Tyr-397 dephosphorylation unknown\", \"How RhoA and Ras pathways are coordinated downstream of neogenin not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Three studies simultaneously expanded RGMa biology into the immune system: RGMa on dendritic cells activates Rap1/ICAM-1-mediated T cell adhesion via neogenin, RGMa repels leukocyte migration in a neogenin-dependent manner, and activated microglia upregulate RGMa to inhibit axonal growth—collectively establishing RGMa–neogenin as a neuroimmune signaling axis.\",\n      \"evidence\": \"DC–T cell co-culture with Rap1 assay and EAE model (anti-RGMa antibody); leukocyte migration assay and peritonitis model in neogenin gene-trap mice; microglia–neuron co-culture with RGMa siRNA and SCI model\",\n      \"pmids\": [\"21423182\", \"21467223\", \"21957482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional programs in T cells not mapped\", \"Whether neogenin on microglia also signals back to neurons unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Biochemical mapping of RGMa proteolytic processing by Furin/SKI-1 and autocatalytic cleavage revealed that multiple fragments (N-RGMa, C-RGMa) all bind neogenin's fibronectin-like domains but engage distinct downstream effectors; separately, RGMa was shown to regulate non-neuronal cell migration via its RGD motif and adhesion via its vWF domain in a neogenin-dependent, BMP-independent manner.\",\n      \"evidence\": \"Mass spectrometry fragment identification, furin/SKI-1 cleavage assays, in vivo electroporation of cleavage mutants; Xenopus animal cap migration/adhesion assays with deletion mutants\",\n      \"pmids\": [\"22340500\", \"22215618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of fragment signaling in vivo unknown\", \"Whether specific fragments dominate in specific tissues not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Crystal structures of the NEO1–RGMB complex revealed a novel protein fold and a pH-dependent 2:2 receptor–ligand architecture that applies to all RGM family members, providing the first atomic-resolution model for RGMa–neogenin signaling.\",\n      \"evidence\": \"X-ray crystallography of NEO1–RGMB complex with functional validation of autocatalytic cleavage\",\n      \"pmids\": [\"23744777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of RGMa specifically (not RGMB) in complex with NEO1 not determined\", \"How conformational changes propagate to the intracellular domain unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that C-RGMa and N-RGMa fragments activate two distinct pathways—C-RGMa via LARG/Rho/ROCK and N-RGMa via γ-secretase/NeICD/LMO4—with each producing different layer-specific targeting errors in the tectum, resolved how a single ligand generates multiple context-dependent outputs through proteolytic diversification.\",\n      \"evidence\": \"In ovo electroporation of fragment constructs and dominant-negative LARG, γ-secretase inhibitor, NeICD overexpression in chick tectum with anterograde tracing\",\n      \"pmids\": [\"26292756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines which fragment predominates at a given synapse unknown\", \"Whether both pathways can operate simultaneously in the same neuron untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that RGMa scaffolds a TGFβ/ALK5/Smad2/3 complex in astrocytes to drive reactive gliosis after stroke revealed a third major signaling mode—distinct from both neogenin-mediated repulsion and BMP co-receptor function—linking RGMa to scar formation.\",\n      \"evidence\": \"Co-IP of RGMa–ALK5–Smad2/3 complex, RGMa siRNA blocking TGFβ1-induced Smad2/3 phosphorylation in primary astrocytes, in vivo MCAO model\",\n      \"pmids\": [\"29396549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RGMa binds ALK5 directly or through an intermediary unclear\", \"Relative contribution of BMP vs. TGFβ arms to glial scar unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that RGMa-induced neogenin glycosylation and intramembrane proteolysis generates a nuclear NeoICD fragment essential for neuroepithelial cell elongation during neurulation provided the mechanistic link between RGMa signaling and the microtubule-dependent cell shape changes underlying neural tube closure.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with NeoICD overexpression rescue, cell transplantation, microtubule immunostaining\",\n      \"pmids\": [\"31399534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets of NeoICD during neurulation not identified\", \"Whether this cleavage event is regulated by specific proteases beyond γ-secretase unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM and X-ray structures of the ternary NEO1–NET1–RGM super-complex revealed that simultaneous ligand binding assembles a trimer-of-trimers that sterically prevents signaling-competent configurations of either pathway, explaining how netrin-1 silences RGMa repulsion and vice versa.\",\n      \"evidence\": \"Cryo-EM/X-ray crystallography of ternary complex, structure-guided mutagenesis, growth cone collapse and neuron migration assays\",\n      \"pmids\": [\"33740419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the super-complex at guidance decision points not demonstrated\", \"Kinetics of complex assembly/disassembly unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Three studies expanded RGMa pathobiology: RGMa on neurons/astrocytes drives macrophage CXCL2 production via neogenin to recruit neutrophils in NMO; RGMa disrupts BBB integrity through BMP2/BMPRII/YAP-mediated tight junction loss; and RGMa promotes VSMC dedifferentiation via Slug to drive neointima formation—demonstrating breadth beyond axon guidance.\",\n      \"evidence\": \"Macrophage stimulation assay and NMO rat model with anti-RGMa mAb; HBMEC RGMa overexpression/knockdown with BMPRII inhibition and YAP activation; VSMC ox-LDL model with Slug siRNA rescue and carotid ligation in ApoE−/− mice\",\n      \"pmids\": [\"35167145\", \"35664003\", \"36089003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CXCL2 regulation is Rap1-dependent or uses a distinct pathway unclear\", \"BBB finding from a single lab awaits independent replication\", \"VSMC dedifferentiation mechanism downstream of Slug not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that RGMa collapses the neuronal actin barrier to promote uptake of misfolded SOD1, with anti-RGMa antibody reducing aggregation and symptoms in ALS mice, identified a novel cell-biological mechanism linking RGMa to proteinopathy spread.\",\n      \"evidence\": \"In vitro actin depolymerization and mutant SOD1 uptake assays with anti-RGMa antibody, in vivo mSOD1 transgenic mouse model\",\n      \"pmids\": [\"37992159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether actin barrier collapse is neogenin-dependent not formally tested\", \"Whether this mechanism generalizes to other misfolded proteins (e.g. TDP-43, α-synuclein) unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how cells coordinate the three major RGMa signaling modes (neogenin repulsion, BMP co-receptor, TGFβ/ALK5 scaffolding) in a context-dependent manner; the precise protease(s) and regulation of RGMa fragment balance in vivo; nuclear targets of NeoICD beyond LMO4; and whether the structural super-complex architecture with netrin-1 operates at in vivo guidance decision points.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model for how cells select among parallel RGMa signaling outputs\", \"In vivo fragment-specific signaling not mapped at single-cell resolution\", \"Therapeutic antibodies target total RGMa—fragment-selective approaches not developed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 19]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 13, 14]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 13, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 7, 9, 18, 19, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 8, 20, 25, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 28]}\n    ],\n    \"complexes\": [\n      \"NEO1-RGMa-NET1 ternary super-complex\",\n      \"RGMa-BMP-BMPRI co-receptor complex\",\n      \"RGMa-ALK5-Smad2/3 complex\"\n    ],\n    \"partners\": [\n      \"NEO1\",\n      \"BMP2\",\n      \"BMP4\",\n      \"ALK5\",\n      \"NTN1\",\n      \"LARG\",\n      \"LMO4\",\n      \"SLUG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}