{"gene":"MDGA1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2017,"finding":"Crystal structure of MDGA1 Ig1-Ig2 in complex with NLGN2 reveals that two MDGA1 molecules each span the entire NLGN2 dimer; MDGA1 Ig1 binds the same region on NLGN2 as neurexins do, establishing that MDGA1 sterically blocks neurexin access to neuroligin-2, thereby inhibiting trans-synaptic bridge formation.","method":"Crystal structure determination + site-directed mutagenesis + binding affinity measurements","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis, replicated in two independent concurrent studies","pmids":["28641112"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of human NL2/MDGA1 Ig1-3 complex reveals a stable 2:2 arrangement with three interaction interfaces; cell-based assays with structure-guided mutants show all three contact patches are required for MDGA1's negative regulation of NL2-mediated synaptogenic activity. MDGA1 Ig1 competes with neurexins for NL2. Despite similar binding affinities to NL1 and NL2 in vitro, MDGA1 selectively associates with NL2 but not NL1 in vivo.","method":"Crystal structure determination + cell-based synaptogenesis assays + site-directed mutagenesis + binding affinity measurements + co-immunoprecipitation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis and multiple orthogonal assays, replicated by concurrent independent study","pmids":["28641111"],"is_preprint":false},{"year":2023,"finding":"MDGA1 ectodomain can adopt both compact and extended 3D conformations that both bind NLGN2; designer mutants at strategic molecular elbows alter the distribution of 3D conformations without changing soluble ectodomain binding affinity to NLGN2, yet in a cellular context these mutants impair NLGN2 binding, reduce capacity to conceal NLGN2 from NRXN1β, and suppress NLGN2-mediated inhibitory presynaptic differentiation — demonstrating that global 3D conformation of the entire MDGA1 ectodomain is required for its function.","method":"Cryo-EM/single-particle analysis of conformational states + designer mutagenesis + cell-based functional assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural analysis combined with functional mutagenesis and cell-based assays, single lab but multiple orthogonal methods","pmids":["36889589"],"is_preprint":false},{"year":2006,"finding":"RNAi-mediated knockdown of MDGA1 in vivo blocks proper radial migration of superficial layer (2/3) cortical neurons, with transfected cells accumulating deep in the cortical plate; this defect is rescued by co-transfection of rat MDGA1, establishing that MDGA1 acts cell-autonomously to control migration of superficial layer cortical neurons.","method":"In utero RNAi electroporation + rescue experiment with rat MDGA1 construct","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular phenotype plus RNAi-rescue control, replicated across multiple RNAi sequences","pmids":["16641224"],"is_preprint":false},{"year":2016,"finding":"MDGA1 co-localizes and forms a complex with gap junction protein Connexin43 in basal progenitor cell membranes of the cortical SVZ; conditional deletion of MDGA1 from basal progenitors reduces their proliferation, decreases SVZ size, causes ectopic positioning of basal progenitors in the cortical plate, and reduces production of cortical layer neurons.","method":"Conditional knockout (floxed allele) + co-immunoprecipitation/co-localization + histological analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined phenotype, co-localization/complex formation shown, single lab","pmids":["26776515"],"is_preprint":false},{"year":2017,"finding":"Genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory (but not excitatory) synapse density and transmission, selectively at perisomatic (but not distal dendritic) inhibitory synapses; MDGA1 is selectively expressed by pyramidal neurons. Mdga1-/- mice show muted responses to neural excitation, resistance to induced seizures, impaired hippocampal LTP, and deficits in spatial and context-dependent learning and memory.","method":"Germline knockout mouse + electrophysiology + immunohistochemistry + behavioral testing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts (electrophysiology, anatomy, behavior), subcellular specificity defined","pmids":["29281813"],"is_preprint":false},{"year":2022,"finding":"The MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP); MDGA1-mediated synaptic disinhibition requires the MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Presynaptic APP in GABAergic interneurons is required for this trans-synaptic mechanism. Overexpression of MDGA1 WT or MAM domain alone (but not MAM-deleted MDGA1) impairs novel object-recognition memory.","method":"Co-immunoprecipitation + domain deletion/overexpression + electrophysiology + behavioral testing + protein infusion experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, functional rescue/loss-of-function, multiple orthogonal methods in single lab","pmids":["35074912"],"is_preprint":false},{"year":2019,"finding":"MDGA1 is an in vivo substrate of the Alzheimer protease BACE1; BACE1 cleaves MDGA1 within its juxtamembrane domain. Inhibition or deletion of BACE1 in primary neurons and mouse brains results in increased full-length MDGA1 protein levels.","method":"Isotope-label quantitative proteomics of BACE1 KO vs. WT mouse brains + immunoblot validation in primary neurons + BACE1 inhibitor treatment","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo substrate identification validated by multiple approaches (proteomics, immunoblot, KO, inhibitor), cleavage site mapped","pmids":["31908000"],"is_preprint":false},{"year":2005,"finding":"Human MDGA1 is a GPI-anchored glycoprotein that localizes to the plasma membrane via the secretory pathway; it is enriched in lipid raft membrane microdomains and undergoes N-glycosylation. GPI anchorage is confirmed by phospholipase C (PI-PLC) cleavage.","method":"PI-PLC treatment + sucrose density gradient fractionation for lipid rafts + glycosylation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and enzymatic cleavage, single lab, multiple biochemical methods","pmids":["15922729"],"is_preprint":false},{"year":2006,"finding":"MDGA1 interacts heterophilically with axon-rich regions primarily through its MAM domain, and interacts with differentiating muscle through its N-terminal Ig domain region, establishing domain-specific binding partners in the developing nervous system.","method":"Domain-deletion binding assays using truncated MDGA1 constructs applied to tissue sections","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-deletion binding assays, single lab, two orthogonal domain truncations tested","pmids":["16782075"],"is_preprint":false},{"year":2010,"finding":"MDGA1 expression increases cell motility and cell-cell adhesion, and decreases adhesion to extracellular matrix proteins (particularly collagen IV) in MDCK cells. Truncation experiments show that Ig domains contribute to motility and collagen IV adhesion reduction, while the MAM domain mediates heterophilic cell-cell adhesion. siRNA silencing of MDGA1 significantly increases adhesion to collagen IV.","method":"Stable overexpression of full-length and truncated MDGA1 + siRNA knockdown + cell migration and adhesion assays","journal":"Cancer microenvironment","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with domain truncations, single lab, functional assays in non-neuronal cells","pmids":["21505559"],"is_preprint":false},{"year":2023,"finding":"Using epitope-tagged MDGA1 knock-in mice, endogenous MDGA1 was found enriched at excitatory (not inhibitory) synapses. shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 caused cell-autonomous impairment of AMPA receptor-mediated (excitatory) synaptic transmission without affecting GABAergic transmission — contradicting previous reports that MDGA1 primarily suppresses inhibitory synapses.","method":"Epitope-tagged knock-in mice + shRNA knockdown + CRISPR/Cas9 KO + slice electrophysiology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous tagging plus CRISPR KO with electrophysiology, single lab, preprint only","pmids":["37720016"],"is_preprint":true},{"year":2024,"finding":"Loss of MDGA1 expression (but not heterozygous MDGA2 deletion) rescues the abnormal cytosolic gephyrin aggregation, reduction in inhibitory synaptic transmission, and exacerbated anxiety behavior in Nlgn2 knockout mice; combined Nlgn2 and MDGA1 deletion causes exacerbated layer-specific loss of gephyrin puncta, demonstrating epistatic interaction between MDGA1 and Nlgn2 at GABAergic synapses in hippocampal CA1.","method":"Double knockout (Nlgn2 KO × Mdga1 KO) + electrophysiology + immunostaining for gephyrin + behavioral analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double KO with multiple orthogonal readouts, single lab","pmids":["39284869"],"is_preprint":false},{"year":2025,"finding":"MDGA1 and Nlgn2 selectively interact in the lateral habenula (LHb); this interaction is elevated following chronic restrained stress. Germline MDGA1 KO increases inhibitory transmission and GABAergic synapse density in the LHb; introducing an Nlgn2 variant incapable of binding MDGA1 similarly enhances inhibitory transmission and synapse density. MDGA1 deficiency in adult LHb confers resistance to chronic stress-induced depressive behaviors.","method":"Co-immunoprecipitation + conditional KO (viral Cre) + Nlgn2 knock-in variant + electrophysiology + immunostaining + behavioral testing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic approaches (KO, re-expression, Nlgn2 binding-deficient KI) with electrophysiology and behavior, single lab","pmids":["39897557"],"is_preprint":false},{"year":2023,"finding":"After spinal nerve ligation, MDGA1 is upregulated in the dorsal horn; MDGA1 knockdown with siRNA normalizes increased GluR1 surface delivery in the synaptosomal membrane fraction, reduces pain hypersensitivity, inhibits the increased neuroligin-2/PSD-95 (excitatory) interaction, and prevents decreased neuroligin-2/Gephyrin (inhibitory) interaction — establishing that upregulated MDGA1 shifts neuroligin-2 from inhibitory toward excitatory scaffolding.","method":"siRNA knockdown in vivo + co-immunoprecipitation + synaptosomal fractionation + Western blot + behavioral pain testing","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with multiple molecular readouts and functional consequence, single lab","pmids":["37955815"],"is_preprint":false},{"year":2025,"finding":"ASD-associated MDGA1 Tyr635Cys/Glu756Gln double mutation disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons, while MDGA1 Val116Met/Ala688Val overexpression alters cortical neuron migration and impairs ultrasonic vocalizations — demonstrating that different missense pairs cause distinct loss-of-function mechanisms.","method":"In utero overexpression + knock-in mouse + electrophysiology + structural analysis + behavioral testing","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutations characterized with structural and functional assays, two distinct phenotypic readouts, single lab","pmids":["41862769"],"is_preprint":false},{"year":2026,"finding":"Using epitope-tagged MDGA1 knock-in mice, endogenous MDGA1 in hippocampal CA1 localizes to dendrites but shows no clear enrichment at excitatory or inhibitory synapses; acute pre- or postsynaptic deletion of MDGA1 does not affect inhibitory or excitatory synaptic transmission in slice electrophysiology, suggesting MDGA1 may transiently inhabit but does not strongly regulate hippocampal synapses in young mice.","method":"Epitope-tagged knock-in mice + conditional acute deletion + slice electrophysiology + immunofluorescence","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous tagging and acute genetic deletion with electrophysiology, single lab; negative synaptic-localization finding","pmids":["41530055"],"is_preprint":false}],"current_model":"MDGA1 is a GPI-anchored, lipid raft-localized cell-surface immunoglobulin/MAM-domain protein that controls cortical neuron migration cell-autonomously, forms a direct cis complex with neuroligin-2 (via its Ig1-Ig2 domains) on the postsynaptic membrane to sterically block neurexin binding and suppress GABAergic synapse formation, interacts via its MAM domain with presynaptic APP to tune inhibitory transmission in a dendrite-compartment-specific manner, and is cleaved in the juxtamembrane region by BACE1 in vivo; its 3D extracellular conformation (compact triangular vs. extended) is critical for its synapse-regulatory function, and loss of MDGA1 leads to increased inhibitory synapse density and transmission, impaired hippocampal LTP, and deficits in learning and memory."},"narrative":{"mechanistic_narrative":"MDGA1 is a GPI-anchored, lipid-raft-localized cell-surface glycoprotein of the immunoglobulin/MAM-domain family that governs cortical neuron migration and the balance of inhibitory versus excitatory synaptic connectivity in the brain [PMID:15922729, PMID:16641224, PMID:29281813]. During corticogenesis it acts cell-autonomously to direct radial migration of superficial-layer neurons [PMID:16641224] and supports basal progenitor proliferation in the subventricular zone in a complex with Connexin43 [PMID:26776515]. At the synapse, MDGA1 forms a direct cis complex with neuroligin-2: crystal and structural studies show its Ig1-Ig2 region binds the neuroligin-2 dimer at the same surface used by neurexins, sterically occluding neurexin access and thereby suppressing trans-synaptic bridge formation and GABAergic synaptogenesis [PMID:28641112, PMID:28641111]. This negative regulation depends on the global 3D conformation of the entire MDGA1 ectodomain rather than ectodomain binding affinity alone [PMID:36889589]. Consistent with this mechanism, MDGA1 loss elevates hippocampal CA1 perisomatic inhibitory synapse density and transmission, impairs LTP, and produces learning and memory deficits [PMID:29281813], and MDGA1 deletion is epistatic to and rescues the synaptic and behavioral phenotypes of Nlgn2-null mice [PMID:39284869]. A separate MAM-domain interaction with presynaptic APP mediates dendrite-compartment-specific disinhibition at distal CA1 dendrites [PMID:35074912]. MDGA1 is cleaved within its juxtamembrane region by the protease BACE1 in vivo, linking its abundance to BACE1 activity [PMID:31908000]. Disease-associated missense mutations disrupt either the synapse-regulatory triangular ectodomain conformation or cortical neuron migration, defining distinct loss-of-function mechanisms relevant to autism spectrum disorder [PMID:41862769].","teleology":[{"year":2005,"claim":"Establishing how MDGA1 is displayed at the cell surface was the first step toward understanding its function; it was shown to be a GPI-anchored, raft-enriched, N-glycosylated plasma membrane protein.","evidence":"PI-PLC cleavage, sucrose density lipid-raft fractionation, and glycosylation assays on human MDGA1","pmids":["15922729"],"confidence":"Medium","gaps":["Does not address binding partners or signaling role","Single lab, non-neuronal biochemical characterization"]},{"year":2006,"claim":"Whether MDGA1 has a developmental role was unknown; loss-of-function in vivo showed it is required cell-autonomously for radial migration of superficial cortical neurons.","evidence":"In utero RNAi electroporation with rat-MDGA1 rescue control","pmids":["16641224"],"confidence":"High","gaps":["Molecular partners driving migration not identified","Does not connect migration to later synaptic functions"]},{"year":2006,"claim":"To define candidate binding modalities, domain-deletion binding assays mapped distinct heterophilic partners to the MAM domain (axon-rich regions) and the Ig domains (differentiating muscle).","evidence":"Truncated MDGA1 constructs applied to developing nervous-system tissue sections","pmids":["16782075"],"confidence":"Medium","gaps":["Molecular identity of the binding partners not determined","Functional consequence of binding not tested"]},{"year":2010,"claim":"The adhesion/motility properties of MDGA1 were probed in epithelial cells, assigning Ig-domain control of motility and ECM (collagen IV) adhesion and MAM-domain control of heterophilic cell-cell adhesion.","evidence":"Stable over- and truncated expression plus siRNA in MDCK cells with migration/adhesion assays","pmids":["21505559"],"confidence":"Medium","gaps":["Non-neuronal system; relevance to brain function unclear","Direct molecular adhesion partners not identified"]},{"year":2016,"claim":"The neurogenic role of MDGA1 was extended to progenitors; it forms a complex with Connexin43 and is required for basal progenitor proliferation and correct positioning.","evidence":"Conditional knockout plus co-IP/co-localization and histology in the cortical SVZ","pmids":["26776515"],"confidence":"Medium","gaps":["Mechanism by which the MDGA1-Cx43 complex controls proliferation unresolved","Single lab"]},{"year":2017,"claim":"The central molecular mechanism — how MDGA1 suppresses inhibitory synapses — was solved structurally: it binds the neuroligin-2 dimer via Ig domains at the neurexin-binding surface, sterically blocking neurexin and inhibiting synaptogenic bridging.","evidence":"Two concurrent crystal structures of MDGA1 Ig domains with NLGN2, structure-guided mutagenesis, binding affinity, cell-based synaptogenesis assays","pmids":["28641112","28641111"],"confidence":"High","gaps":["In vitro affinity similar for NLGN1 and NLGN2 but in vivo selectivity for NLGN2 not mechanistically explained","Does not establish in vivo synaptic phenotype"]},{"year":2017,"claim":"Whether the in vitro steric mechanism operates in the brain was tested; germline knockout selectively elevated perisomatic inhibitory synapses and transmission and impaired LTP, learning, and memory.","evidence":"Germline KO mouse with electrophysiology, immunohistochemistry, and behavioral testing","pmids":["29281813"],"confidence":"High","gaps":["Excitatory synapses reported unaffected — later contradicted","Subcellular basis of perisomatic selectivity not fully resolved"]},{"year":2019,"claim":"How MDGA1 abundance is post-translationally controlled was addressed: it is an in vivo BACE1 substrate cleaved in its juxtamembrane domain, linking MDGA1 levels to BACE1 activity.","evidence":"Quantitative proteomics of BACE1 KO vs WT brain, immunoblot validation, and BACE1 inhibitor treatment in neurons","pmids":["31908000"],"confidence":"High","gaps":["Functional consequence of cleavage on synaptic regulation not directly demonstrated","Whether cleavage releases a signaling fragment unknown"]},{"year":2022,"claim":"A second trans-synaptic mechanism was uncovered: the MAM domain binds presynaptic APP to mediate compartment-specific disinhibition at distal CA1 dendrites.","evidence":"Reciprocal co-IP with domain mapping, domain-deletion/overexpression, electrophysiology, protein infusion, and behavior","pmids":["35074912"],"confidence":"High","gaps":["How APP and NLGN2 pathways are spatially segregated within a neuron not fully resolved","Single lab"]},{"year":2023,"claim":"The structural determinant of function was refined: the global 3D ectodomain conformation (compact vs extended), not soluble affinity, is required to conceal NLGN2 and suppress synaptogenesis.","evidence":"Cryo-EM single-particle conformational analysis with designer elbow mutants and cell-based assays","pmids":["36889589"],"confidence":"High","gaps":["How conformation is regulated in vivo unknown","Conformational states not visualized at the membrane"]},{"year":2023,"claim":"Endogenous targeting and the inhibitory-synapse model were challenged: epitope-tagged knock-in revealed enrichment at excitatory synapses and a cell-autonomous requirement for AMPA-receptor transmission without affecting GABAergic transmission.","evidence":"Epitope-tagged knock-in mice, shRNA, CRISPR/Cas9 KO, slice electrophysiology (preprint)","pmids":["37720016"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Directly contradicts prior inhibitory-synapse findings — reconciliation unresolved"]},{"year":2023,"claim":"A pathological context for MDGA1's scaffolding role emerged: after nerve injury its upregulation shifts neuroligin-2 from inhibitory toward excitatory scaffolding to drive pain hypersensitivity.","evidence":"In vivo siRNA, co-IP, synaptosomal fractionation, Western blot, and behavioral pain testing after spinal nerve ligation","pmids":["37955815"],"confidence":"Medium","gaps":["Molecular mechanism of the inhibitory-to-excitatory scaffold switch not defined","Single lab"]},{"year":2024,"claim":"Genetic epistasis was established in vivo: MDGA1 deletion rescues gephyrin aggregation, inhibitory transmission, and anxiety phenotypes of Nlgn2 KO mice, confirming MDGA1 acts on the NLGN2 pathway at GABAergic synapses.","evidence":"Nlgn2 KO x Mdga1 KO double knockout with electrophysiology, gephyrin immunostaining, behavior","pmids":["39284869"],"confidence":"Medium","gaps":["Layer-specific effects of combined deletion not mechanistically explained","Single lab"]},{"year":2025,"claim":"The MDGA1-NLGN2 axis was shown to operate in a circuit relevant to mood, with stress-regulated interaction in the lateral habenula and MDGA1 loss conferring resistance to stress-induced depressive behavior.","evidence":"Co-IP, viral conditional KO, Nlgn2 binding-deficient knock-in, electrophysiology, immunostaining, behavior","pmids":["39897557"],"confidence":"Medium","gaps":["Upstream signal driving stress-induced interaction increase unknown","Single lab"]},{"year":2025,"claim":"Disease relevance was tied directly to mechanism: distinct ASD-associated missense pairs cause loss of function either by disrupting the triangular ectodomain conformation (loss of GABAergic synapse regulation) or by altering cortical migration.","evidence":"In utero overexpression, knock-in mice, structural analysis, electrophysiology, behavioral testing","pmids":["41862769"],"confidence":"Medium","gaps":["Patient-level genetic causality not established by these models","Single lab"]},{"year":2026,"claim":"The strength of MDGA1's hippocampal synaptic regulation was re-examined; endogenous protein was dendritic without clear synaptic enrichment and acute deletion did not alter transmission, indicating its synaptic role may be transient in young mice.","evidence":"Epitope-tagged knock-in mice, acute conditional deletion, slice electrophysiology, immunofluorescence","pmids":["41530055"],"confidence":"Medium","gaps":["Discrepancy with germline-KO phenotypes (developmental vs acute) unresolved","Age- and circuit-dependence of function not mapped"]},{"year":null,"claim":"It remains unresolved whether MDGA1 predominantly restrains inhibitory synapses (via NLGN2 steric blockade) or shapes excitatory transmission, and how developmental versus acute requirements and tagging/deletion strategies account for the conflicting endogenous-localization and phenotype data.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Excitatory vs inhibitory primacy unreconciled across labs","Developmental versus acute requirement undefined","In vivo regulation of ectodomain conformation and BACE1 cleavage on synaptic output unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,6]}],"complexes":[],"partners":["NLGN2","APP","NRXN1","GJA1","BACE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFP4","full_name":"MAM domain-containing glycosylphosphatidylinositol anchor protein 1","aliases":["GPI and MAM protein","GPIM","Glycosylphosphatidylinositol-MAM","MAM domain-containing protein 3"],"length_aa":955,"mass_kda":105.8,"function":"Required for radial migration of cortical neurons in the superficial layer of the neocortex (By similarity). Plays a role in the formation or maintenance of inhibitory synapses. May function by inhibiting the activity of NLGN2","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NFP4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MDGA1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MDGA1","total_profiled":1310},"omim":[{"mim_id":"611128","title":"MAM DOMAIN-CONTAINING GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR 2; MDGA2","url":"https://www.omim.org/entry/611128"},{"mim_id":"609626","title":"MAM DOMAIN-CONTAINING GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR 1; MDGA1","url":"https://www.omim.org/entry/609626"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":80.5}],"url":"https://www.proteinatlas.org/search/MDGA1"},"hgnc":{"alias_symbol":["GPIM","MAMDC3"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFP4","domains":[{"cath_id":"2.60.40.10","chopping":"22-128","consensus_level":"high","plddt":80.0252,"start":22,"end":128},{"cath_id":"2.60.40.10","chopping":"132-231","consensus_level":"medium","plddt":89.9933,"start":132,"end":231},{"cath_id":"2.60.40.10","chopping":"240-325","consensus_level":"medium","plddt":93.711,"start":240,"end":325},{"cath_id":"2.60.40.10","chopping":"327-436","consensus_level":"medium","plddt":89.8866,"start":327,"end":436},{"cath_id":"2.60.40.10","chopping":"438-535","consensus_level":"medium","plddt":91.4497,"start":438,"end":535},{"cath_id":"2.60.40.10","chopping":"539-584_595-630","consensus_level":"medium","plddt":91.6272,"start":539,"end":630},{"cath_id":"2.60.40.10","chopping":"636-737","consensus_level":"medium","plddt":86.9192,"start":636,"end":737},{"cath_id":"2.60.120.200","chopping":"751-912","consensus_level":"high","plddt":86.9222,"start":751,"end":912}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFP4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFP4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFP4-F1-predicted_aligned_error_v6.png","plddt_mean":84.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MDGA1","jax_strain_url":"https://www.jax.org/strain/search?query=MDGA1"},"sequence":{"accession":"Q8NFP4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFP4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFP4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFP4"}},"corpus_meta":[{"pmid":"18384059","id":"PMC_18384059","title":"Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene.","date":"2008","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18384059","citation_count":103,"is_preprint":false},{"pmid":"28641112","id":"PMC_28641112","title":"Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges.","date":"2017","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/28641112","citation_count":62,"is_preprint":false},{"pmid":"28641111","id":"PMC_28641111","title":"Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex.","date":"2017","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/28641111","citation_count":59,"is_preprint":false},{"pmid":"16641224","id":"PMC_16641224","title":"Radial migration of superficial layer cortical neurons controlled by novel Ig cell adhesion molecule MDGA1.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/37720016","citation_count":7,"is_preprint":false},{"pmid":"37955815","id":"PMC_37955815","title":"Upregulation of Spinal MDGA1 in Rats After Nerve Injury Alters Interactions Between Neuroligin-2 and Postsynaptic Scaffolding Proteins and Increases GluR1 Subunit Surface Delivery in the Spinal Cord Dorsal Horn.","date":"2023","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/37955815","citation_count":4,"is_preprint":false},{"pmid":"39273620","id":"PMC_39273620","title":"Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39273620","citation_count":3,"is_preprint":false},{"pmid":"40058148","id":"PMC_40058148","title":"Preliminary findings of DNA hypermethylation of MDGA1 in idiopathic restless legs 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\"method\": \"Crystal structure determination + site-directed mutagenesis + binding affinity measurements\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis, replicated in two independent concurrent studies\",\n      \"pmids\": [\"28641112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of human NL2/MDGA1 Ig1-3 complex reveals a stable 2:2 arrangement with three interaction interfaces; cell-based assays with structure-guided mutants show all three contact patches are required for MDGA1's negative regulation of NL2-mediated synaptogenic activity. MDGA1 Ig1 competes with neurexins for NL2. Despite similar binding affinities to NL1 and NL2 in vitro, MDGA1 selectively associates with NL2 but not NL1 in vivo.\",\n      \"method\": \"Crystal structure determination + cell-based synaptogenesis assays + site-directed mutagenesis + binding affinity measurements + co-immunoprecipitation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis and multiple orthogonal assays, replicated by concurrent independent study\",\n      \"pmids\": [\"28641111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MDGA1 ectodomain can adopt both compact and extended 3D conformations that both bind NLGN2; designer mutants at strategic molecular elbows alter the distribution of 3D conformations without changing soluble ectodomain binding affinity to NLGN2, yet in a cellular context these mutants impair NLGN2 binding, reduce capacity to conceal NLGN2 from NRXN1β, and suppress NLGN2-mediated inhibitory presynaptic differentiation — demonstrating that global 3D conformation of the entire MDGA1 ectodomain is required for its function.\",\n      \"method\": \"Cryo-EM/single-particle analysis of conformational states + designer mutagenesis + cell-based functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis combined with functional mutagenesis and cell-based assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36889589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNAi-mediated knockdown of MDGA1 in vivo blocks proper radial migration of superficial layer (2/3) cortical neurons, with transfected cells accumulating deep in the cortical plate; this defect is rescued by co-transfection of rat MDGA1, establishing that MDGA1 acts cell-autonomously to control migration of superficial layer cortical neurons.\",\n      \"method\": \"In utero RNAi electroporation + rescue experiment with rat MDGA1 construct\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular phenotype plus RNAi-rescue control, replicated across multiple RNAi sequences\",\n      \"pmids\": [\"16641224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDGA1 co-localizes and forms a complex with gap junction protein Connexin43 in basal progenitor cell membranes of the cortical SVZ; conditional deletion of MDGA1 from basal progenitors reduces their proliferation, decreases SVZ size, causes ectopic positioning of basal progenitors in the cortical plate, and reduces production of cortical layer neurons.\",\n      \"method\": \"Conditional knockout (floxed allele) + co-immunoprecipitation/co-localization + histological analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined phenotype, co-localization/complex formation shown, single lab\",\n      \"pmids\": [\"26776515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory (but not excitatory) synapse density and transmission, selectively at perisomatic (but not distal dendritic) inhibitory synapses; MDGA1 is selectively expressed by pyramidal neurons. Mdga1-/- mice show muted responses to neural excitation, resistance to induced seizures, impaired hippocampal LTP, and deficits in spatial and context-dependent learning and memory.\",\n      \"method\": \"Germline knockout mouse + electrophysiology + immunohistochemistry + behavioral testing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts (electrophysiology, anatomy, behavior), subcellular specificity defined\",\n      \"pmids\": [\"29281813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP); MDGA1-mediated synaptic disinhibition requires the MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Presynaptic APP in GABAergic interneurons is required for this trans-synaptic mechanism. Overexpression of MDGA1 WT or MAM domain alone (but not MAM-deleted MDGA1) impairs novel object-recognition memory.\",\n      \"method\": \"Co-immunoprecipitation + domain deletion/overexpression + electrophysiology + behavioral testing + protein infusion experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, functional rescue/loss-of-function, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"35074912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MDGA1 is an in vivo substrate of the Alzheimer protease BACE1; BACE1 cleaves MDGA1 within its juxtamembrane domain. Inhibition or deletion of BACE1 in primary neurons and mouse brains results in increased full-length MDGA1 protein levels.\",\n      \"method\": \"Isotope-label quantitative proteomics of BACE1 KO vs. WT mouse brains + immunoblot validation in primary neurons + BACE1 inhibitor treatment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo substrate identification validated by multiple approaches (proteomics, immunoblot, KO, inhibitor), cleavage site mapped\",\n      \"pmids\": [\"31908000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human MDGA1 is a GPI-anchored glycoprotein that localizes to the plasma membrane via the secretory pathway; it is enriched in lipid raft membrane microdomains and undergoes N-glycosylation. GPI anchorage is confirmed by phospholipase C (PI-PLC) cleavage.\",\n      \"method\": \"PI-PLC treatment + sucrose density gradient fractionation for lipid rafts + glycosylation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and enzymatic cleavage, single lab, multiple biochemical methods\",\n      \"pmids\": [\"15922729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MDGA1 interacts heterophilically with axon-rich regions primarily through its MAM domain, and interacts with differentiating muscle through its N-terminal Ig domain region, establishing domain-specific binding partners in the developing nervous system.\",\n      \"method\": \"Domain-deletion binding assays using truncated MDGA1 constructs applied to tissue sections\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-deletion binding assays, single lab, two orthogonal domain truncations tested\",\n      \"pmids\": [\"16782075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MDGA1 expression increases cell motility and cell-cell adhesion, and decreases adhesion to extracellular matrix proteins (particularly collagen IV) in MDCK cells. Truncation experiments show that Ig domains contribute to motility and collagen IV adhesion reduction, while the MAM domain mediates heterophilic cell-cell adhesion. siRNA silencing of MDGA1 significantly increases adhesion to collagen IV.\",\n      \"method\": \"Stable overexpression of full-length and truncated MDGA1 + siRNA knockdown + cell migration and adhesion assays\",\n      \"journal\": \"Cancer microenvironment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with domain truncations, single lab, functional assays in non-neuronal cells\",\n      \"pmids\": [\"21505559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Using epitope-tagged MDGA1 knock-in mice, endogenous MDGA1 was found enriched at excitatory (not inhibitory) synapses. shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 caused cell-autonomous impairment of AMPA receptor-mediated (excitatory) synaptic transmission without affecting GABAergic transmission — contradicting previous reports that MDGA1 primarily suppresses inhibitory synapses.\",\n      \"method\": \"Epitope-tagged knock-in mice + shRNA knockdown + CRISPR/Cas9 KO + slice electrophysiology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous tagging plus CRISPR KO with electrophysiology, single lab, preprint only\",\n      \"pmids\": [\"37720016\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of MDGA1 expression (but not heterozygous MDGA2 deletion) rescues the abnormal cytosolic gephyrin aggregation, reduction in inhibitory synaptic transmission, and exacerbated anxiety behavior in Nlgn2 knockout mice; combined Nlgn2 and MDGA1 deletion causes exacerbated layer-specific loss of gephyrin puncta, demonstrating epistatic interaction between MDGA1 and Nlgn2 at GABAergic synapses in hippocampal CA1.\",\n      \"method\": \"Double knockout (Nlgn2 KO × Mdga1 KO) + electrophysiology + immunostaining for gephyrin + behavioral analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double KO with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"39284869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA1 and Nlgn2 selectively interact in the lateral habenula (LHb); this interaction is elevated following chronic restrained stress. Germline MDGA1 KO increases inhibitory transmission and GABAergic synapse density in the LHb; introducing an Nlgn2 variant incapable of binding MDGA1 similarly enhances inhibitory transmission and synapse density. MDGA1 deficiency in adult LHb confers resistance to chronic stress-induced depressive behaviors.\",\n      \"method\": \"Co-immunoprecipitation + conditional KO (viral Cre) + Nlgn2 knock-in variant + electrophysiology + immunostaining + behavioral testing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic approaches (KO, re-expression, Nlgn2 binding-deficient KI) with electrophysiology and behavior, single lab\",\n      \"pmids\": [\"39897557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"After spinal nerve ligation, MDGA1 is upregulated in the dorsal horn; MDGA1 knockdown with siRNA normalizes increased GluR1 surface delivery in the synaptosomal membrane fraction, reduces pain hypersensitivity, inhibits the increased neuroligin-2/PSD-95 (excitatory) interaction, and prevents decreased neuroligin-2/Gephyrin (inhibitory) interaction — establishing that upregulated MDGA1 shifts neuroligin-2 from inhibitory toward excitatory scaffolding.\",\n      \"method\": \"siRNA knockdown in vivo + co-immunoprecipitation + synaptosomal fractionation + Western blot + behavioral pain testing\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with multiple molecular readouts and functional consequence, single lab\",\n      \"pmids\": [\"37955815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASD-associated MDGA1 Tyr635Cys/Glu756Gln double mutation disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons, while MDGA1 Val116Met/Ala688Val overexpression alters cortical neuron migration and impairs ultrasonic vocalizations — demonstrating that different missense pairs cause distinct loss-of-function mechanisms.\",\n      \"method\": \"In utero overexpression + knock-in mouse + electrophysiology + structural analysis + behavioral testing\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutations characterized with structural and functional assays, two distinct phenotypic readouts, single lab\",\n      \"pmids\": [\"41862769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Using epitope-tagged MDGA1 knock-in mice, endogenous MDGA1 in hippocampal CA1 localizes to dendrites but shows no clear enrichment at excitatory or inhibitory synapses; acute pre- or postsynaptic deletion of MDGA1 does not affect inhibitory or excitatory synaptic transmission in slice electrophysiology, suggesting MDGA1 may transiently inhabit but does not strongly regulate hippocampal synapses in young mice.\",\n      \"method\": \"Epitope-tagged knock-in mice + conditional acute deletion + slice electrophysiology + immunofluorescence\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous tagging and acute genetic deletion with electrophysiology, single lab; negative synaptic-localization finding\",\n      \"pmids\": [\"41530055\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MDGA1 is a GPI-anchored, lipid raft-localized cell-surface immunoglobulin/MAM-domain protein that controls cortical neuron migration cell-autonomously, forms a direct cis complex with neuroligin-2 (via its Ig1-Ig2 domains) on the postsynaptic membrane to sterically block neurexin binding and suppress GABAergic synapse formation, interacts via its MAM domain with presynaptic APP to tune inhibitory transmission in a dendrite-compartment-specific manner, and is cleaved in the juxtamembrane region by BACE1 in vivo; its 3D extracellular conformation (compact triangular vs. extended) is critical for its synapse-regulatory function, and loss of MDGA1 leads to increased inhibitory synapse density and transmission, impaired hippocampal LTP, and deficits in learning and memory.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MDGA1 is a GPI-anchored, lipid-raft-localized cell-surface glycoprotein of the immunoglobulin/MAM-domain family that governs cortical neuron migration and the balance of inhibitory versus excitatory synaptic connectivity in the brain [#8, #3, #5]. During corticogenesis it acts cell-autonomously to direct radial migration of superficial-layer neurons [#3] and supports basal progenitor proliferation in the subventricular zone in a complex with Connexin43 [#4]. At the synapse, MDGA1 forms a direct cis complex with neuroligin-2: crystal and structural studies show its Ig1-Ig2 region binds the neuroligin-2 dimer at the same surface used by neurexins, sterically occluding neurexin access and thereby suppressing trans-synaptic bridge formation and GABAergic synaptogenesis [#0, #1]. This negative regulation depends on the global 3D conformation of the entire MDGA1 ectodomain rather than ectodomain binding affinity alone [#2]. Consistent with this mechanism, MDGA1 loss elevates hippocampal CA1 perisomatic inhibitory synapse density and transmission, impairs LTP, and produces learning and memory deficits [#5], and MDGA1 deletion is epistatic to and rescues the synaptic and behavioral phenotypes of Nlgn2-null mice [#12]. A separate MAM-domain interaction with presynaptic APP mediates dendrite-compartment-specific disinhibition at distal CA1 dendrites [#6]. MDGA1 is cleaved within its juxtamembrane region by the protease BACE1 in vivo, linking its abundance to BACE1 activity [#7]. Disease-associated missense mutations disrupt either the synapse-regulatory triangular ectodomain conformation or cortical neuron migration, defining distinct loss-of-function mechanisms relevant to autism spectrum disorder [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing how MDGA1 is displayed at the cell surface was the first step toward understanding its function; it was shown to be a GPI-anchored, raft-enriched, N-glycosylated plasma membrane protein.\",\n      \"evidence\": \"PI-PLC cleavage, sucrose density lipid-raft fractionation, and glycosylation assays on human MDGA1\",\n      \"pmids\": [\"15922729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address binding partners or signaling role\", \"Single lab, non-neuronal biochemical characterization\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether MDGA1 has a developmental role was unknown; loss-of-function in vivo showed it is required cell-autonomously for radial migration of superficial cortical neurons.\",\n      \"evidence\": \"In utero RNAi electroporation with rat-MDGA1 rescue control\",\n      \"pmids\": [\"16641224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners driving migration not identified\", \"Does not connect migration to later synaptic functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"To define candidate binding modalities, domain-deletion binding assays mapped distinct heterophilic partners to the MAM domain (axon-rich regions) and the Ig domains (differentiating muscle).\",\n      \"evidence\": \"Truncated MDGA1 constructs applied to developing nervous-system tissue sections\",\n      \"pmids\": [\"16782075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the binding partners not determined\", \"Functional consequence of binding not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The adhesion/motility properties of MDGA1 were probed in epithelial cells, assigning Ig-domain control of motility and ECM (collagen IV) adhesion and MAM-domain control of heterophilic cell-cell adhesion.\",\n      \"evidence\": \"Stable over- and truncated expression plus siRNA in MDCK cells with migration/adhesion assays\",\n      \"pmids\": [\"21505559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-neuronal system; relevance to brain function unclear\", \"Direct molecular adhesion partners not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The neurogenic role of MDGA1 was extended to progenitors; it forms a complex with Connexin43 and is required for basal progenitor proliferation and correct positioning.\",\n      \"evidence\": \"Conditional knockout plus co-IP/co-localization and histology in the cortical SVZ\",\n      \"pmids\": [\"26776515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the MDGA1-Cx43 complex controls proliferation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The central molecular mechanism — how MDGA1 suppresses inhibitory synapses — was solved structurally: it binds the neuroligin-2 dimer via Ig domains at the neurexin-binding surface, sterically blocking neurexin and inhibiting synaptogenic bridging.\",\n      \"evidence\": \"Two concurrent crystal structures of MDGA1 Ig domains with NLGN2, structure-guided mutagenesis, binding affinity, cell-based synaptogenesis assays\",\n      \"pmids\": [\"28641112\", \"28641111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro affinity similar for NLGN1 and NLGN2 but in vivo selectivity for NLGN2 not mechanistically explained\", \"Does not establish in vivo synaptic phenotype\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether the in vitro steric mechanism operates in the brain was tested; germline knockout selectively elevated perisomatic inhibitory synapses and transmission and impaired LTP, learning, and memory.\",\n      \"evidence\": \"Germline KO mouse with electrophysiology, immunohistochemistry, and behavioral testing\",\n      \"pmids\": [\"29281813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Excitatory synapses reported unaffected — later contradicted\", \"Subcellular basis of perisomatic selectivity not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How MDGA1 abundance is post-translationally controlled was addressed: it is an in vivo BACE1 substrate cleaved in its juxtamembrane domain, linking MDGA1 levels to BACE1 activity.\",\n      \"evidence\": \"Quantitative proteomics of BACE1 KO vs WT brain, immunoblot validation, and BACE1 inhibitor treatment in neurons\",\n      \"pmids\": [\"31908000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cleavage on synaptic regulation not directly demonstrated\", \"Whether cleavage releases a signaling fragment unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A second trans-synaptic mechanism was uncovered: the MAM domain binds presynaptic APP to mediate compartment-specific disinhibition at distal CA1 dendrites.\",\n      \"evidence\": \"Reciprocal co-IP with domain mapping, domain-deletion/overexpression, electrophysiology, protein infusion, and behavior\",\n      \"pmids\": [\"35074912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How APP and NLGN2 pathways are spatially segregated within a neuron not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The structural determinant of function was refined: the global 3D ectodomain conformation (compact vs extended), not soluble affinity, is required to conceal NLGN2 and suppress synaptogenesis.\",\n      \"evidence\": \"Cryo-EM single-particle conformational analysis with designer elbow mutants and cell-based assays\",\n      \"pmids\": [\"36889589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformation is regulated in vivo unknown\", \"Conformational states not visualized at the membrane\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Endogenous targeting and the inhibitory-synapse model were challenged: epitope-tagged knock-in revealed enrichment at excitatory synapses and a cell-autonomous requirement for AMPA-receptor transmission without affecting GABAergic transmission.\",\n      \"evidence\": \"Epitope-tagged knock-in mice, shRNA, CRISPR/Cas9 KO, slice electrophysiology (preprint)\",\n      \"pmids\": [\"37720016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Directly contradicts prior inhibitory-synapse findings — reconciliation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A pathological context for MDGA1's scaffolding role emerged: after nerve injury its upregulation shifts neuroligin-2 from inhibitory toward excitatory scaffolding to drive pain hypersensitivity.\",\n      \"evidence\": \"In vivo siRNA, co-IP, synaptosomal fractionation, Western blot, and behavioral pain testing after spinal nerve ligation\",\n      \"pmids\": [\"37955815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the inhibitory-to-excitatory scaffold switch not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic epistasis was established in vivo: MDGA1 deletion rescues gephyrin aggregation, inhibitory transmission, and anxiety phenotypes of Nlgn2 KO mice, confirming MDGA1 acts on the NLGN2 pathway at GABAergic synapses.\",\n      \"evidence\": \"Nlgn2 KO x Mdga1 KO double knockout with electrophysiology, gephyrin immunostaining, behavior\",\n      \"pmids\": [\"39284869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Layer-specific effects of combined deletion not mechanistically explained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The MDGA1-NLGN2 axis was shown to operate in a circuit relevant to mood, with stress-regulated interaction in the lateral habenula and MDGA1 loss conferring resistance to stress-induced depressive behavior.\",\n      \"evidence\": \"Co-IP, viral conditional KO, Nlgn2 binding-deficient knock-in, electrophysiology, immunostaining, behavior\",\n      \"pmids\": [\"39897557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal driving stress-induced interaction increase unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Disease relevance was tied directly to mechanism: distinct ASD-associated missense pairs cause loss of function either by disrupting the triangular ectodomain conformation (loss of GABAergic synapse regulation) or by altering cortical migration.\",\n      \"evidence\": \"In utero overexpression, knock-in mice, structural analysis, electrophysiology, behavioral testing\",\n      \"pmids\": [\"41862769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Patient-level genetic causality not established by these models\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The strength of MDGA1's hippocampal synaptic regulation was re-examined; endogenous protein was dendritic without clear synaptic enrichment and acute deletion did not alter transmission, indicating its synaptic role may be transient in young mice.\",\n      \"evidence\": \"Epitope-tagged knock-in mice, acute conditional deletion, slice electrophysiology, immunofluorescence\",\n      \"pmids\": [\"41530055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with germline-KO phenotypes (developmental vs acute) unresolved\", \"Age- and circuit-dependence of function not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether MDGA1 predominantly restrains inhibitory synapses (via NLGN2 steric blockade) or shapes excitatory transmission, and how developmental versus acute requirements and tagging/deletion strategies account for the conflicting endogenous-localization and phenotype data.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Excitatory vs inhibitory primacy unreconciled across labs\", \"Developmental versus acute requirement undefined\", \"In vivo regulation of ectodomain conformation and BACE1 cleavage on synaptic output unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NLGN2\",\n      \"APP\",\n      \"NRXN1\",\n      \"GJA1\",\n      \"BACE1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}