{"gene":"MDGA1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2017,"finding":"MDGA1 Ig1-Ig2 binds NLGN2 with nanomolar affinity; crystal structure of the complex shows two MDGA1 Ig1-Ig2 molecules spanning the entire NLGN2 dimer, with Ig1 occupying the same region on NLGN2 as neurexins do, establishing that MDGA1 sterically blocks neurexin access to neuroligin-2 to regulate trans-synaptic bridge formation.","method":"Crystal structure determination, nanomolar binding affinity measurement, site-directed mutagenesis confirming interaction interface","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation, replicated by concurrent independent study","pmids":["28641112"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of human NL2/MDGA1 Ig1-3 complex reveal a 2:2 arrangement with three interaction interfaces; all three contact patches are required for MDGA1's negative regulation of NL2-mediated synaptogenic activity; MDGA1 Ig1 domain competes with neurexins for NL2 binding; despite similar affinities for NL1 and NL2 in vitro, MDGA1 selectively associates with NL2 but not NL1 in vivo.","method":"Crystal structure determination, cell-based synaptogenesis assays with structure-guided site-directed mutants, binding affinity measurements","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with cell-based functional validation using mutagenesis, replicated by concurrent independent study","pmids":["28641111"],"is_preprint":false},{"year":2017,"finding":"Genetic deletion of MDGA1 in vivo selectively elevates hippocampal CA1 inhibitory (but not excitatory) synapse density and transmission; MDGA1 is expressed by pyramidal neurons and regulates perisomatic but not distal dendritic inhibitory synapses; Mdga1-/- mice show resistance to induced seizures, impaired hippocampal LTP, and deficits in spatial and context-dependent learning and memory.","method":"Germline knockout mouse, electrophysiology, immunostaining, behavioral tests (Morris water maze, contextual fear conditioning), seizure induction","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal phenotypic readouts (electrophysiology, behavior, histology)","pmids":["29281813"],"is_preprint":false},{"year":2006,"finding":"RNAi knockdown of MDGA1 in vivo blocks proper radial migration of superficial layer (2/3) cortical neurons; the migration defect is rescued by cotransfection of rat MDGA1, confirming cell-autonomous requirement for MDGA1 in cortical neuron migration.","method":"In utero electroporation of RNAi constructs, GFP reporter tracking, rescue experiment with rat MDGA1 construct","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific phenotypic readout confirmed by rescue experiment","pmids":["16641224"],"is_preprint":false},{"year":2006,"finding":"MDGA1 interacts heterophilically with axon-rich regions primarily through its MAM domain, and with differentiating muscle through its N-terminal Ig domain region, suggesting domain-specific binding partners in the developing nervous system.","method":"Binding assays with distinct truncated protein constructs (MAM domain vs. Ig domain regions) in embryonic chick spinal cord","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 3 — domain-mapping binding assay, single lab, single method","pmids":["16782075"],"is_preprint":false},{"year":2005,"finding":"Human MDGA1 is a GPI-anchored protein that localizes to the plasma membrane via the secretory pathway; it resides specifically in lipid raft microdomains and undergoes N-glycosylation as a post-translational modification; GPI anchor is cleavable by phospholipase C (PI-PLC).","method":"Cell fractionation, detergent-resistant membrane isolation, PI-PLC treatment, glycosylation assays, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical fractionation and localization with functional modifications confirmed","pmids":["15922729"],"is_preprint":false},{"year":2016,"finding":"MDGA1 is expressed in basal progenitor (BP) cell membranes where it co-localizes and forms a complex with the gap junction protein Connexin43; deletion of MDGA1 from BPs reduces BP proliferation, reduces SVZ size, causes ectopic BP positioning, and diminishes cortical layer neuron production.","method":"Conditional knockout using floxed MDGA1 allele, co-immunoprecipitation with Connexin43, immunostaining, BrdU proliferation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotype plus co-IP identifying complex partner","pmids":["26776515"],"is_preprint":false},{"year":2019,"finding":"MDGA1 is a substrate of the Alzheimer's disease protease BACE1 in vivo; BACE1 cleaves MDGA1 within its juxtamembrane domain; inhibition or deletion of BACE1 in primary neurons causes accumulation of full-length MDGA1.","method":"Isotope-label quantitative proteomics of BACE1 KO vs. wild-type mouse brains, immunoblot validation in primary neurons and mouse brains, cleavage site mapping","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo proteomics plus biochemical validation with KO model identifying cleavage site","pmids":["31908000"],"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 interneurons is required for MDGA1-mediated disinhibition; overexpression of wild-type or MAM-only MDGA1, but not MAM-deleted MDGA1, impairs novel object-recognition memory.","method":"Co-immunoprecipitation, domain deletion mutants, electrophysiology, behavioral testing, protein infusion experiments","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with domain mapping, electrophysiology, and behavioral rescue/impairment experiments","pmids":["35074912"],"is_preprint":false},{"year":2023,"finding":"WT MDGA1 can adopt both compact and extended 3D conformations while binding NLGN2; designer mutants targeting molecular elbows alter the distribution of 3D conformations without changing NLGN2 binding affinity of soluble ectodomains, but in cellular context impair binding to NLGN2, decrease capacity to conceal NLGN2 from NRXN1β, and suppress NLGN2-mediated inhibitory presynaptic differentiation, demonstrating that global 3D conformation of the full MDGA1 ectodomain is critical for function.","method":"Electron microscopy of conformational states, surface plasmon resonance, cell-based binding assays, presynaptic differentiation assays with designer mutants","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — structural analysis combined with mutagenesis and multiple cell-based functional assays","pmids":["36889589"],"is_preprint":false},{"year":2024,"finding":"Loss of MDGA1 (but not heterozygous MDGA2 deletion) ameliorates abnormal cytosolic gephyrin aggregation, reduction in inhibitory synaptic transmission, and exacerbated anxiety in Nlgn2 knockout mice; combined Nlgn2 and MDGA1 deletion causes exacerbated layer-specific loss of gephyrin puncta, establishing MDGA1 as a functional modulator of NLGN2-dependent gephyrin scaffold assembly and GABAergic synapse organization.","method":"Double knockout mouse genetics (epistasis), electrophysiology, immunostaining for gephyrin puncta, behavioral tests","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double KO plus orthogonal electrophysiology and imaging","pmids":["39284869"],"is_preprint":false},{"year":2023,"finding":"Endogenous MDGA1 (using epitope-tagged knock-in mice) is enriched at excitatory, not inhibitory, synapses; shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 causes cell-autonomous impairment of AMPA receptor-mediated excitatory synaptic transmission without affecting GABAergic transmission.","method":"Epitope-tagged knock-in mice, shRNA knockdown, CRISPR/Cas9 knockout, slice electrophysiology","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — knock-in localization plus KO electrophysiology, but preprint","pmids":["37720016"],"is_preprint":true},{"year":2023,"finding":"After spinal nerve ligation, upregulated spinal MDGA1 alters neuroligin-2 interactions: it increases the excitatory scaffolding interaction between NL2 and PSD-95, decreases the inhibitory interaction between NL2 and Gephyrin, and increases surface delivery of GluR1 AMPA receptor subunits in the dorsal horn; MDGA1 siRNA knockdown reverses these changes and reduces pain hypersensitivity.","method":"Co-immunoprecipitation, synaptosomal fractionation, western blot, intrathecal siRNA injection, behavioral pain testing","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional siRNA knockdown, single lab","pmids":["37955815"],"is_preprint":false},{"year":2025,"finding":"MDGA1 and Nlgn2 selectively interact in the lateral habenula (LHb); their interaction is elevated following chronic restraint stress; germline MDGA1 knockout or introduction of an Nlgn2 variant incapable of binding MDGA1 increases inhibitory transmission and GABAergic synapse density in LHb; MDGA1 deficiency in adult LHb confers resistance to stress-induced depressive behaviors, establishing MDGA1–Nlgn2 interaction as a regulator of inhibitory synapse strength in depression-relevant circuitry.","method":"Conditional knockout/re-expression using viral Cre, knockin Nlgn2 variant, electrophysiology, immunostaining, chemogenetic LH activation, behavioral depression tests","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic approaches (KO, re-expression, variant knockin) with orthogonal electrophysiology and behavior","pmids":["39897557"],"is_preprint":false},{"year":2010,"finding":"MDGA1 overexpression in MDCK cells increases cell motility and cell-cell adhesion but reduces adhesion to extracellular matrix proteins (especially collagen IV); domain dissection shows both Ig and MAM domains contribute to motility, while MAM domain mediates heterophilic cell-cell adhesion; siRNA silencing of MDGA1 increases adhesion to collagen IV.","method":"Stable cell line overexpression of full-length and domain-truncated constructs, siRNA knockdown, migration assays, adhesion assays","journal":"Cancer microenvironment","confidence":"Medium","confidence_rationale":"Tier 3 — domain-mapping functional assays in non-neuronal cells, single lab","pmids":["21505559"],"is_preprint":false},{"year":2025,"finding":"The MDGA1 Tyr635Cys/Glu756Gln double mutation disrupts the triangular extracellular domain structure of MDGA1 and abolishes its ability to impact GABAergic synapses; in utero overexpression of the Val116Met/Ala688Val variant alters cortical neuron migration; male knockin mice carrying Tyr636Cys/Glu751Gln show impaired GABAergic synaptic strength and ASD-relevant behavioral deficits reversible by bazedoxifene.","method":"Structural analysis of mutant proteins, in utero electroporation, electrophysiology in cultured neurons and CA1 slices, knockin mouse behavioral phenotyping, proteomics","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 — structural disruption linked to loss of synaptic function via multiple orthogonal approaches","pmids":["41862769"],"is_preprint":false}],"current_model":"MDGA1 is a GPI-anchored cell surface IgCAM that localizes to lipid rafts and acts as a synaptic organizer by binding neuroligin-2 (via its Ig1-Ig2 domains) in cis on the postsynaptic membrane, sterically blocking trans-synaptic neurexin–neuroligin bridges to suppress GABAergic synapse formation; its full ectodomain adopts a compact triangular conformation required for function, it interacts with APP via its MAM domain to mediate compartment-specific disinhibition, is cleaved in its juxtamembrane domain by BACE1, complexes with Connexin43 in basal progenitors to regulate cortical SVZ neurogenesis, and acts cell-autonomously to control radial migration of superficial cortical neurons."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that MDGA1 is a GPI-anchored, lipid-raft-resident glycoprotein resolved how it is tethered to the cell surface and positioned within membrane microdomains relevant for signaling.","evidence":"Cell fractionation, detergent-resistant membrane isolation, PI-PLC treatment, and glycosylation assays in human cells","pmids":["15922729"],"confidence":"Medium","gaps":["Functional consequence of lipid-raft localization uncharacterized","Identity of signaling partners in raft microdomains unknown"]},{"year":2006,"claim":"Demonstrating that MDGA1 knockdown arrests radial migration of superficial cortical neurons—rescued by exogenous MDGA1—established a cell-autonomous developmental role independent of its later synaptic functions.","evidence":"In utero electroporation of RNAi with GFP tracking and rescue with rat MDGA1 construct","pmids":["16641224"],"confidence":"High","gaps":["Downstream effectors mediating migration were not identified","Relationship between migration role and synaptic organizer function unclear"]},{"year":2006,"claim":"Domain-mapping binding assays showed that the MAM domain and Ig domain regions mediate distinct heterophilic interactions with axon-rich and muscle regions, establishing that MDGA1 uses different extracellular domains for context-dependent binding.","evidence":"Truncated protein binding assays in embryonic chick spinal cord","pmids":["16782075"],"confidence":"Medium","gaps":["Specific binding partners for each domain were not identified","Single species/single method limits generalizability"]},{"year":2016,"claim":"Discovery that MDGA1 complexes with Connexin43 in basal progenitors and that its conditional deletion reduces progenitor proliferation and cortical neuron production revealed a non-synaptic developmental function in SVZ neurogenesis.","evidence":"Conditional knockout with floxed MDGA1 allele, co-immunoprecipitation with Connexin43, BrdU proliferation assay","pmids":["26776515"],"confidence":"High","gaps":["Mechanism by which MDGA1–Connexin43 interaction promotes proliferation is unknown","Whether this complex involves gap junction channel function was not tested"]},{"year":2017,"claim":"Two independent crystal structures resolved how MDGA1 suppresses inhibitory synaptogenesis: two MDGA1 molecules bind the neuroligin-2 dimer through three Ig1–Ig3 contact interfaces, with Ig1 directly competing with neurexins for the same binding site on neuroligin-2, providing an atomic-resolution mechanism for steric occlusion.","evidence":"Crystal structures of MDGA1–NLGN2 complexes with mutagenesis validation and cell-based synaptogenesis assays from two independent groups","pmids":["28641112","28641111"],"confidence":"High","gaps":["Why MDGA1 selectively associates with NLGN2 over NLGN1 in vivo despite similar in vitro affinities remained unexplained","Whether conformational dynamics of the full ectodomain beyond Ig1-3 matter was unknown"]},{"year":2017,"claim":"Germline knockout established that MDGA1 loss selectively elevates perisomatic inhibitory synapse density and GABAergic transmission in hippocampal CA1 without affecting excitatory synapses, linking the structural mechanism to circuit-level and behavioral outcomes including seizure resistance and memory deficits.","evidence":"Mdga1 knockout mouse with electrophysiology, immunostaining, behavioral testing (Morris water maze, contextual fear conditioning, seizure induction)","pmids":["29281813"],"confidence":"High","gaps":["Why perisomatic but not distal dendritic inhibitory synapses are affected was unexplained","Compensation by MDGA2 was not assessed"]},{"year":2019,"claim":"Identification of MDGA1 as a BACE1 substrate cleaved in its juxtamembrane domain introduced regulated proteolysis as a mechanism controlling MDGA1 surface levels and potentially its synaptic function.","evidence":"Quantitative proteomics of BACE1 KO vs. WT mouse brains, immunoblot validation in primary neurons, cleavage site mapping","pmids":["31908000"],"confidence":"High","gaps":["Functional consequence of BACE1 cleavage on inhibitory synapse regulation not tested","Whether cleavage is activity-dependent is unknown"]},{"year":2022,"claim":"Demonstrating that the MDGA1 MAM domain directly binds amyloid precursor protein and that presynaptic APP in interneurons is required for MDGA1-mediated disinhibition at distal dendrites revealed a trans-synaptic signaling axis for compartment-specific inhibitory synapse regulation.","evidence":"Co-immunoprecipitation, domain deletion mutants, electrophysiology, behavioral testing, protein infusion","pmids":["35074912"],"confidence":"High","gaps":["Whether APP–MDGA1 interaction is regulated by BACE1 cleavage of either partner is unknown","Mechanism by which this interaction suppresses inhibitory synapses at distal dendrites is not resolved"]},{"year":2023,"claim":"Electron microscopy and designer mutants revealed that the full MDGA1 ectodomain samples compact and extended conformations, and that the compact triangular conformation is essential for concealing neuroligin-2 from neurexin in a cellular context, even though soluble ectodomain binding affinity is preserved in mutants—establishing that global 3D shape, not just local binding interfaces, gates function.","evidence":"Electron microscopy, surface plasmon resonance, cell-based binding and presynaptic differentiation assays with conformation-altering mutants","pmids":["36889589"],"confidence":"High","gaps":["In vivo relevance of conformational regulation not tested at the time","What controls the equilibrium between compact and extended states is unknown"]},{"year":2023,"claim":"In a neuropathic pain model, upregulated spinal MDGA1 shifts neuroligin-2 interactions from inhibitory (gephyrin) to excitatory (PSD-95) scaffolding and increases surface AMPA receptors, with MDGA1 knockdown reversing pain hypersensitivity—extending MDGA1 function beyond development to adult spinal cord plasticity.","evidence":"Co-immunoprecipitation, synaptosomal fractionation, intrathecal siRNA, behavioral pain testing after spinal nerve ligation","pmids":["37955815"],"confidence":"Medium","gaps":["Single lab finding; independent replication needed","Whether MDGA1 directly engages PSD-95 or indirectly re-routes NL2 is unclear"]},{"year":2024,"claim":"Genetic epistasis with Nlgn2 knockout demonstrated that MDGA1 loss ameliorates gephyrin aggregation defects and anxiety-like behavior caused by Nlgn2 deletion, while double deletion exacerbates layer-specific gephyrin puncta loss, formally establishing MDGA1 as a modulator of NLGN2-dependent gephyrin scaffold assembly.","evidence":"Double knockout mouse genetics, electrophysiology, gephyrin immunostaining, behavioral anxiety tests","pmids":["39284869"],"confidence":"High","gaps":["Molecular mechanism by which MDGA1 influences gephyrin aggregation independently of neurexin–NLGN2 bridging is unclear","Layer-specific differences in double KO phenotype not mechanistically explained"]},{"year":2025,"claim":"MDGA1–NLGN2 interaction in the lateral habenula is elevated by chronic stress, and disrupting this interaction (by MDGA1 knockout or NLGN2 binding-deficient knockin) increases inhibitory transmission and confers resilience to stress-induced depressive behavior, extending the MDGA1 mechanism to mood-related circuitry.","evidence":"Conditional knockout/re-expression via viral Cre, Nlgn2 variant knockin, electrophysiology, chemogenetics, behavioral depression tests","pmids":["39897557"],"confidence":"High","gaps":["How chronic stress upregulates the MDGA1–NLGN2 interaction is unknown","Whether BACE1 cleavage of MDGA1 modulates this stress-sensitive interaction is not addressed"]},{"year":2025,"claim":"Disease-associated MDGA1 mutations that disrupt the triangular ectodomain conformation abolish GABAergic synapse regulation and produce ASD-relevant behavioral deficits in knockin mice, directly linking the structural mechanism to neurodevelopmental disease and validating the conformational requirement in vivo.","evidence":"Structural analysis of mutant proteins, in utero electroporation, slice electrophysiology, knockin mouse behavioral phenotyping, proteomics","pmids":["41862769"],"confidence":"High","gaps":["Whether pharmacological restoration of ectodomain conformation is feasible beyond bazedoxifene is untested","Proteomics-identified downstream changes not functionally validated"]},{"year":null,"claim":"Major open questions include: what controls the equilibrium between compact and extended MDGA1 conformations, how BACE1-mediated cleavage feeds back on inhibitory synapse regulation, the basis of in vivo selectivity for NLGN2 over NLGN1, and how MDGA1's developmental roles in migration and progenitor proliferation relate mechanistically to its synaptic organizer function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanism linking conformational dynamics to specific signaling or activity-dependent triggers","BACE1 cleavage functional consequences not characterized","In vivo NLGN2 selectivity mechanism unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,10,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,2,10,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,9]}],"complexes":[],"partners":["NLGN2","APP","GJA1","BACE1","NRXN1"],"other_free_text":[]},"mechanistic_narrative":"MDGA1 is a GPI-anchored immunoglobulin superfamily cell adhesion molecule that functions as a negative regulator of inhibitory synaptogenesis by binding neuroligin-2 in cis on the postsynaptic membrane and sterically occluding neurexin access, thereby suppressing GABAergic synapse formation and gephyrin scaffold assembly [PMID:28641112, PMID:28641111, PMID:39284869]. Crystal structures reveal that two MDGA1 molecules span the neuroligin-2 dimer via Ig1–Ig3 domains, with the compact triangular conformation of the full ectodomain required for functional concealment of neuroligin-2 from neurexin-1β; disease-associated mutations that disrupt this conformation abolish synaptic regulation and produce ASD-relevant behavioral deficits in knockin mice [PMID:36889589, PMID:41862769]. Beyond inhibitory synapse control, MDGA1 interacts with amyloid precursor protein through its MAM domain to mediate compartment-specific disinhibition at distal dendrites, is proteolytically cleaved by BACE1 in its juxtamembrane region, and acts cell-autonomously during cortical development to regulate radial neuronal migration and basal progenitor proliferation through a complex with Connexin43 [PMID:35074912, PMID:31908000, PMID:16641224, PMID:26776515]. Genetic deletion of MDGA1 selectively increases hippocampal inhibitory synapse density and transmission, confers seizure resistance, impairs LTP and spatial memory, and in the lateral habenula protects against stress-induced depressive behaviors [PMID:29281813, PMID:39897557]."},"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. 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for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16641224","citation_count":53,"is_preprint":false},{"pmid":"29281813","id":"PMC_29281813","title":"Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29281813","citation_count":49,"is_preprint":false},{"pmid":"21146959","id":"PMC_21146959","title":"The MDGA1 gene confers risk to schizophrenia and bipolar disorder.","date":"2010","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/21146959","citation_count":36,"is_preprint":false},{"pmid":"16959869","id":"PMC_16959869","title":"Novel IgCAM, MDGA1, expressed in unique cortical area- and layer-specific patterns and transiently by distinct forebrain populations of Cajal-Retzius neurons.","date":"2006","source":"Cerebral cortex (New York, N.Y. : 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2000)","url":"https://pubmed.ncbi.nlm.nih.gov/19422017","citation_count":12,"is_preprint":false},{"pmid":"36247836","id":"PMC_36247836","title":"Differential expression of MDGA1 in major depressive disorder.","date":"2022","source":"Brain, behavior, & immunity - health","url":"https://pubmed.ncbi.nlm.nih.gov/36247836","citation_count":11,"is_preprint":false},{"pmid":"36889589","id":"PMC_36889589","title":"Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36889589","citation_count":10,"is_preprint":false},{"pmid":"21505559","id":"PMC_21505559","title":"Expression of Human MDGA1 Increases Cell Motility and Cell-Cell Adhesion and Reduces Adhesion to Extracellular Matrix Proteins in MDCK Cells.","date":"2010","source":"Cancer microenvironment : official journal of the International Cancer Microenvironment 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nanomolar binding affinity measurement, site-directed mutagenesis confirming interaction interface\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation, replicated by concurrent independent study\",\n      \"pmids\": [\"28641112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of human NL2/MDGA1 Ig1-3 complex reveal a 2:2 arrangement with three interaction interfaces; all three contact patches are required for MDGA1's negative regulation of NL2-mediated synaptogenic activity; MDGA1 Ig1 domain competes with neurexins for NL2 binding; despite similar affinities for NL1 and NL2 in vitro, MDGA1 selectively associates with NL2 but not NL1 in vivo.\",\n      \"method\": \"Crystal structure determination, cell-based synaptogenesis assays with structure-guided site-directed mutants, binding affinity measurements\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with cell-based functional validation using mutagenesis, replicated by concurrent independent study\",\n      \"pmids\": [\"28641111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic deletion of MDGA1 in vivo selectively elevates hippocampal CA1 inhibitory (but not excitatory) synapse density and transmission; MDGA1 is expressed by pyramidal neurons and regulates perisomatic but not distal dendritic inhibitory synapses; Mdga1-/- mice show resistance to induced seizures, impaired hippocampal LTP, and deficits in spatial and context-dependent learning and memory.\",\n      \"method\": \"Germline knockout mouse, electrophysiology, immunostaining, behavioral tests (Morris water maze, contextual fear conditioning), seizure induction\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal phenotypic readouts (electrophysiology, behavior, histology)\",\n      \"pmids\": [\"29281813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNAi knockdown of MDGA1 in vivo blocks proper radial migration of superficial layer (2/3) cortical neurons; the migration defect is rescued by cotransfection of rat MDGA1, confirming cell-autonomous requirement for MDGA1 in cortical neuron migration.\",\n      \"method\": \"In utero electroporation of RNAi constructs, GFP reporter tracking, rescue experiment with rat MDGA1 construct\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific phenotypic readout confirmed by rescue experiment\",\n      \"pmids\": [\"16641224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MDGA1 interacts heterophilically with axon-rich regions primarily through its MAM domain, and with differentiating muscle through its N-terminal Ig domain region, suggesting domain-specific binding partners in the developing nervous system.\",\n      \"method\": \"Binding assays with distinct truncated protein constructs (MAM domain vs. Ig domain regions) in embryonic chick spinal cord\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — domain-mapping binding assay, single lab, single method\",\n      \"pmids\": [\"16782075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human MDGA1 is a GPI-anchored protein that localizes to the plasma membrane via the secretory pathway; it resides specifically in lipid raft microdomains and undergoes N-glycosylation as a post-translational modification; GPI anchor is cleavable by phospholipase C (PI-PLC).\",\n      \"method\": \"Cell fractionation, detergent-resistant membrane isolation, PI-PLC treatment, glycosylation assays, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical fractionation and localization with functional modifications confirmed\",\n      \"pmids\": [\"15922729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDGA1 is expressed in basal progenitor (BP) cell membranes where it co-localizes and forms a complex with the gap junction protein Connexin43; deletion of MDGA1 from BPs reduces BP proliferation, reduces SVZ size, causes ectopic BP positioning, and diminishes cortical layer neuron production.\",\n      \"method\": \"Conditional knockout using floxed MDGA1 allele, co-immunoprecipitation with Connexin43, immunostaining, BrdU proliferation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype plus co-IP identifying complex partner\",\n      \"pmids\": [\"26776515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MDGA1 is a substrate of the Alzheimer's disease protease BACE1 in vivo; BACE1 cleaves MDGA1 within its juxtamembrane domain; inhibition or deletion of BACE1 in primary neurons causes accumulation of full-length MDGA1.\",\n      \"method\": \"Isotope-label quantitative proteomics of BACE1 KO vs. wild-type mouse brains, immunoblot validation in primary neurons and mouse brains, cleavage site mapping\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo proteomics plus biochemical validation with KO model identifying cleavage site\",\n      \"pmids\": [\"31908000\"],\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 interneurons is required for MDGA1-mediated disinhibition; overexpression of wild-type or MAM-only MDGA1, but not MAM-deleted MDGA1, impairs novel object-recognition memory.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, electrophysiology, behavioral testing, protein infusion experiments\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with domain mapping, electrophysiology, and behavioral rescue/impairment experiments\",\n      \"pmids\": [\"35074912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WT MDGA1 can adopt both compact and extended 3D conformations while binding NLGN2; designer mutants targeting molecular elbows alter the distribution of 3D conformations without changing NLGN2 binding affinity of soluble ectodomains, but in cellular context impair binding to NLGN2, decrease capacity to conceal NLGN2 from NRXN1β, and suppress NLGN2-mediated inhibitory presynaptic differentiation, demonstrating that global 3D conformation of the full MDGA1 ectodomain is critical for function.\",\n      \"method\": \"Electron microscopy of conformational states, surface plasmon resonance, cell-based binding assays, presynaptic differentiation assays with designer mutants\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural analysis combined with mutagenesis and multiple cell-based functional assays\",\n      \"pmids\": [\"36889589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of MDGA1 (but not heterozygous MDGA2 deletion) ameliorates abnormal cytosolic gephyrin aggregation, reduction in inhibitory synaptic transmission, and exacerbated anxiety in Nlgn2 knockout mice; combined Nlgn2 and MDGA1 deletion causes exacerbated layer-specific loss of gephyrin puncta, establishing MDGA1 as a functional modulator of NLGN2-dependent gephyrin scaffold assembly and GABAergic synapse organization.\",\n      \"method\": \"Double knockout mouse genetics (epistasis), electrophysiology, immunostaining for gephyrin puncta, behavioral tests\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double KO plus orthogonal electrophysiology and imaging\",\n      \"pmids\": [\"39284869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endogenous MDGA1 (using epitope-tagged knock-in mice) is enriched at excitatory, not inhibitory, synapses; shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 causes cell-autonomous impairment of AMPA receptor-mediated excitatory synaptic transmission without affecting GABAergic transmission.\",\n      \"method\": \"Epitope-tagged knock-in mice, shRNA knockdown, CRISPR/Cas9 knockout, slice electrophysiology\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knock-in localization plus KO electrophysiology, but preprint\",\n      \"pmids\": [\"37720016\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"After spinal nerve ligation, upregulated spinal MDGA1 alters neuroligin-2 interactions: it increases the excitatory scaffolding interaction between NL2 and PSD-95, decreases the inhibitory interaction between NL2 and Gephyrin, and increases surface delivery of GluR1 AMPA receptor subunits in the dorsal horn; MDGA1 siRNA knockdown reverses these changes and reduces pain hypersensitivity.\",\n      \"method\": \"Co-immunoprecipitation, synaptosomal fractionation, western blot, intrathecal siRNA injection, behavioral pain testing\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional siRNA knockdown, single lab\",\n      \"pmids\": [\"37955815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA1 and Nlgn2 selectively interact in the lateral habenula (LHb); their interaction is elevated following chronic restraint stress; germline MDGA1 knockout or introduction of an Nlgn2 variant incapable of binding MDGA1 increases inhibitory transmission and GABAergic synapse density in LHb; MDGA1 deficiency in adult LHb confers resistance to stress-induced depressive behaviors, establishing MDGA1–Nlgn2 interaction as a regulator of inhibitory synapse strength in depression-relevant circuitry.\",\n      \"method\": \"Conditional knockout/re-expression using viral Cre, knockin Nlgn2 variant, electrophysiology, immunostaining, chemogenetic LH activation, behavioral depression tests\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic approaches (KO, re-expression, variant knockin) with orthogonal electrophysiology and behavior\",\n      \"pmids\": [\"39897557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MDGA1 overexpression in MDCK cells increases cell motility and cell-cell adhesion but reduces adhesion to extracellular matrix proteins (especially collagen IV); domain dissection shows both Ig and MAM domains contribute to motility, while MAM domain mediates heterophilic cell-cell adhesion; siRNA silencing of MDGA1 increases adhesion to collagen IV.\",\n      \"method\": \"Stable cell line overexpression of full-length and domain-truncated constructs, siRNA knockdown, migration assays, adhesion assays\",\n      \"journal\": \"Cancer microenvironment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — domain-mapping functional assays in non-neuronal cells, single lab\",\n      \"pmids\": [\"21505559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The MDGA1 Tyr635Cys/Glu756Gln double mutation disrupts the triangular extracellular domain structure of MDGA1 and abolishes its ability to impact GABAergic synapses; in utero overexpression of the Val116Met/Ala688Val variant alters cortical neuron migration; male knockin mice carrying Tyr636Cys/Glu751Gln show impaired GABAergic synaptic strength and ASD-relevant behavioral deficits reversible by bazedoxifene.\",\n      \"method\": \"Structural analysis of mutant proteins, in utero electroporation, electrophysiology in cultured neurons and CA1 slices, knockin mouse behavioral phenotyping, proteomics\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural disruption linked to loss of synaptic function via multiple orthogonal approaches\",\n      \"pmids\": [\"41862769\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MDGA1 is a GPI-anchored cell surface IgCAM that localizes to lipid rafts and acts as a synaptic organizer by binding neuroligin-2 (via its Ig1-Ig2 domains) in cis on the postsynaptic membrane, sterically blocking trans-synaptic neurexin–neuroligin bridges to suppress GABAergic synapse formation; its full ectodomain adopts a compact triangular conformation required for function, it interacts with APP via its MAM domain to mediate compartment-specific disinhibition, is cleaved in its juxtamembrane domain by BACE1, complexes with Connexin43 in basal progenitors to regulate cortical SVZ neurogenesis, and acts cell-autonomously to control radial migration of superficial cortical neurons.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MDGA1 is a GPI-anchored immunoglobulin superfamily cell adhesion molecule that functions as a negative regulator of inhibitory synaptogenesis by binding neuroligin-2 in cis on the postsynaptic membrane and sterically occluding neurexin access, thereby suppressing GABAergic synapse formation and gephyrin scaffold assembly [PMID:28641112, PMID:28641111, PMID:39284869]. Crystal structures reveal that two MDGA1 molecules span the neuroligin-2 dimer via Ig1–Ig3 domains, with the compact triangular conformation of the full ectodomain required for functional concealment of neuroligin-2 from neurexin-1β; disease-associated mutations that disrupt this conformation abolish synaptic regulation and produce ASD-relevant behavioral deficits in knockin mice [PMID:36889589, PMID:41862769]. Beyond inhibitory synapse control, MDGA1 interacts with amyloid precursor protein through its MAM domain to mediate compartment-specific disinhibition at distal dendrites, is proteolytically cleaved by BACE1 in its juxtamembrane region, and acts cell-autonomously during cortical development to regulate radial neuronal migration and basal progenitor proliferation through a complex with Connexin43 [PMID:35074912, PMID:31908000, PMID:16641224, PMID:26776515]. Genetic deletion of MDGA1 selectively increases hippocampal inhibitory synapse density and transmission, confers seizure resistance, impairs LTP and spatial memory, and in the lateral habenula protects against stress-induced depressive behaviors [PMID:29281813, PMID:39897557].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that MDGA1 is a GPI-anchored, lipid-raft-resident glycoprotein resolved how it is tethered to the cell surface and positioned within membrane microdomains relevant for signaling.\",\n      \"evidence\": \"Cell fractionation, detergent-resistant membrane isolation, PI-PLC treatment, and glycosylation assays in human cells\",\n      \"pmids\": [\"15922729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of lipid-raft localization uncharacterized\", \"Identity of signaling partners in raft microdomains unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that MDGA1 knockdown arrests radial migration of superficial cortical neurons—rescued by exogenous MDGA1—established a cell-autonomous developmental role independent of its later synaptic functions.\",\n      \"evidence\": \"In utero electroporation of RNAi with GFP tracking and rescue with rat MDGA1 construct\",\n      \"pmids\": [\"16641224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors mediating migration were not identified\", \"Relationship between migration role and synaptic organizer function unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Domain-mapping binding assays showed that the MAM domain and Ig domain regions mediate distinct heterophilic interactions with axon-rich and muscle regions, establishing that MDGA1 uses different extracellular domains for context-dependent binding.\",\n      \"evidence\": \"Truncated protein binding assays in embryonic chick spinal cord\",\n      \"pmids\": [\"16782075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific binding partners for each domain were not identified\", \"Single species/single method limits generalizability\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that MDGA1 complexes with Connexin43 in basal progenitors and that its conditional deletion reduces progenitor proliferation and cortical neuron production revealed a non-synaptic developmental function in SVZ neurogenesis.\",\n      \"evidence\": \"Conditional knockout with floxed MDGA1 allele, co-immunoprecipitation with Connexin43, BrdU proliferation assay\",\n      \"pmids\": [\"26776515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MDGA1–Connexin43 interaction promotes proliferation is unknown\", \"Whether this complex involves gap junction channel function was not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two independent crystal structures resolved how MDGA1 suppresses inhibitory synaptogenesis: two MDGA1 molecules bind the neuroligin-2 dimer through three Ig1–Ig3 contact interfaces, with Ig1 directly competing with neurexins for the same binding site on neuroligin-2, providing an atomic-resolution mechanism for steric occlusion.\",\n      \"evidence\": \"Crystal structures of MDGA1–NLGN2 complexes with mutagenesis validation and cell-based synaptogenesis assays from two independent groups\",\n      \"pmids\": [\"28641112\", \"28641111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why MDGA1 selectively associates with NLGN2 over NLGN1 in vivo despite similar in vitro affinities remained unexplained\", \"Whether conformational dynamics of the full ectodomain beyond Ig1-3 matter was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Germline knockout established that MDGA1 loss selectively elevates perisomatic inhibitory synapse density and GABAergic transmission in hippocampal CA1 without affecting excitatory synapses, linking the structural mechanism to circuit-level and behavioral outcomes including seizure resistance and memory deficits.\",\n      \"evidence\": \"Mdga1 knockout mouse with electrophysiology, immunostaining, behavioral testing (Morris water maze, contextual fear conditioning, seizure induction)\",\n      \"pmids\": [\"29281813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why perisomatic but not distal dendritic inhibitory synapses are affected was unexplained\", \"Compensation by MDGA2 was not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of MDGA1 as a BACE1 substrate cleaved in its juxtamembrane domain introduced regulated proteolysis as a mechanism controlling MDGA1 surface levels and potentially its synaptic function.\",\n      \"evidence\": \"Quantitative proteomics of BACE1 KO vs. WT mouse brains, immunoblot validation in primary neurons, cleavage site mapping\",\n      \"pmids\": [\"31908000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of BACE1 cleavage on inhibitory synapse regulation not tested\", \"Whether cleavage is activity-dependent is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that the MDGA1 MAM domain directly binds amyloid precursor protein and that presynaptic APP in interneurons is required for MDGA1-mediated disinhibition at distal dendrites revealed a trans-synaptic signaling axis for compartment-specific inhibitory synapse regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, domain deletion mutants, electrophysiology, behavioral testing, protein infusion\",\n      \"pmids\": [\"35074912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APP–MDGA1 interaction is regulated by BACE1 cleavage of either partner is unknown\", \"Mechanism by which this interaction suppresses inhibitory synapses at distal dendrites is not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Electron microscopy and designer mutants revealed that the full MDGA1 ectodomain samples compact and extended conformations, and that the compact triangular conformation is essential for concealing neuroligin-2 from neurexin in a cellular context, even though soluble ectodomain binding affinity is preserved in mutants—establishing that global 3D shape, not just local binding interfaces, gates function.\",\n      \"evidence\": \"Electron microscopy, surface plasmon resonance, cell-based binding and presynaptic differentiation assays with conformation-altering mutants\",\n      \"pmids\": [\"36889589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of conformational regulation not tested at the time\", \"What controls the equilibrium between compact and extended states is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In a neuropathic pain model, upregulated spinal MDGA1 shifts neuroligin-2 interactions from inhibitory (gephyrin) to excitatory (PSD-95) scaffolding and increases surface AMPA receptors, with MDGA1 knockdown reversing pain hypersensitivity—extending MDGA1 function beyond development to adult spinal cord plasticity.\",\n      \"evidence\": \"Co-immunoprecipitation, synaptosomal fractionation, intrathecal siRNA, behavioral pain testing after spinal nerve ligation\",\n      \"pmids\": [\"37955815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding; independent replication needed\", \"Whether MDGA1 directly engages PSD-95 or indirectly re-routes NL2 is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic epistasis with Nlgn2 knockout demonstrated that MDGA1 loss ameliorates gephyrin aggregation defects and anxiety-like behavior caused by Nlgn2 deletion, while double deletion exacerbates layer-specific gephyrin puncta loss, formally establishing MDGA1 as a modulator of NLGN2-dependent gephyrin scaffold assembly.\",\n      \"evidence\": \"Double knockout mouse genetics, electrophysiology, gephyrin immunostaining, behavioral anxiety tests\",\n      \"pmids\": [\"39284869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which MDGA1 influences gephyrin aggregation independently of neurexin–NLGN2 bridging is unclear\", \"Layer-specific differences in double KO phenotype not mechanistically explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MDGA1–NLGN2 interaction in the lateral habenula is elevated by chronic stress, and disrupting this interaction (by MDGA1 knockout or NLGN2 binding-deficient knockin) increases inhibitory transmission and confers resilience to stress-induced depressive behavior, extending the MDGA1 mechanism to mood-related circuitry.\",\n      \"evidence\": \"Conditional knockout/re-expression via viral Cre, Nlgn2 variant knockin, electrophysiology, chemogenetics, behavioral depression tests\",\n      \"pmids\": [\"39897557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chronic stress upregulates the MDGA1–NLGN2 interaction is unknown\", \"Whether BACE1 cleavage of MDGA1 modulates this stress-sensitive interaction is not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Disease-associated MDGA1 mutations that disrupt the triangular ectodomain conformation abolish GABAergic synapse regulation and produce ASD-relevant behavioral deficits in knockin mice, directly linking the structural mechanism to neurodevelopmental disease and validating the conformational requirement in vivo.\",\n      \"evidence\": \"Structural analysis of mutant proteins, in utero electroporation, slice electrophysiology, knockin mouse behavioral phenotyping, proteomics\",\n      \"pmids\": [\"41862769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pharmacological restoration of ectodomain conformation is feasible beyond bazedoxifene is untested\", \"Proteomics-identified downstream changes not functionally validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: what controls the equilibrium between compact and extended MDGA1 conformations, how BACE1-mediated cleavage feeds back on inhibitory synapse regulation, the basis of in vivo selectivity for NLGN2 over NLGN1, and how MDGA1's developmental roles in migration and progenitor proliferation relate mechanistically to its synaptic organizer function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism linking conformational dynamics to specific signaling or activity-dependent triggers\", \"BACE1 cleavage functional consequences not characterized\", \"In vivo NLGN2 selectivity mechanism unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 2, 10, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NLGN2\",\n      \"APP\",\n      \"GJA1\",\n      \"BACE1\",\n      \"NRXN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}