{"gene":"EPHA7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2005,"finding":"EphA7-mediated signaling on neocortical axons controls the within-nucleus topography of corticothalamic (CT) projections in the thalamus, as demonstrated by in utero electroporation-mediated mis-expression of EphA7 in cortical neurons, which disrupted CT topography without altering thalamocortical projection topography.","method":"In utero electroporation-mediated gene transfer, axon tracing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct in vivo gain-of-function with electroporation, specific phenotypic readout (CT vs TC topography dissociation), single lab but rigorous design","pmids":["16301174"],"is_preprint":false},{"year":2005,"finding":"HOXA13 and HOXD13 directly bind to cis-regulatory sites in the EphA7 promoter in vivo (ChIP in developing mouse limbs) and activate EphA7 transcription; mutation of the HOXA13/HOXD13 binding site abolishes activation, establishing EphA7 as a direct downstream target of paralog group 13 Hox proteins during limb development.","method":"ChIP in developing mouse limbs, promoter reporter assays, mutagenesis of binding sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo ChIP combined with promoter mutagenesis and luciferase assays, multiple orthogonal methods in one study","pmids":["16314414"],"is_preprint":false},{"year":2006,"finding":"EphA7 produces two isoforms from the same gene: a full-length receptor tyrosine kinase (TK+) and a truncated isoform lacking the kinase domain (TK-). The proportions of these isoforms shift during cortical development from a more repulsive (TK+ dominant) mix embryonically to a more permissive (TK- dominant) mix postnatally; in EphA7-/- mice, the distribution of ephrin-A5 is altered and the somatosensory cortex area is reduced, establishing EphA7 as a regulator of cortical domain formation and ephrin-A5 distribution.","method":"EphA7-/- mouse analysis, RNA expression profiling, in vivo functional studies, cortical area measurements","journal":"The Journal of comparative neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple quantitative phenotypic readouts and isoform expression analysis, single lab with orthogonal methods","pmids":["16615124"],"is_preprint":false},{"year":1999,"finding":"EphA7 encodes both a TK+ (full-length) and a TK- (kinase-domain-lacking) isoform with strikingly different distributions in adult mouse brain: TK+ immunoreactivity is on neuropil/axonal arborizations throughout telencephalon, while TK- is conspicuous on cell bodies and proximal dendrites of specific neuronal types; the TK- isoform may act as a dominant-negative antagonist to ensure TK+ responds only to signals at growing axon/dendrite tips.","method":"Isoform-specific antibodies, immunohistochemistry in adult mouse brain","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemical localization with isoform-specific antibodies, clear compartmentalization finding, single lab, no functional rescue experiment","pmids":["10640696"],"is_preprint":false},{"year":2007,"finding":"ALL1/AF4 and ALL1/AF9 fusion proteins directly occupy the EphA7 promoter (ChIP) and transcriptionally upregulate EphA7 in leukemic cells; siRNA-mediated knockdown of ALL1/AF4 in t(4;11) cells downregulates EphA7; EphA7 upregulation is accompanied by ERK phosphorylation, and ERK inhibition induces apoptosis specifically in t(4;11) leukemic cells.","method":"ChIP, siRNA knockdown, quantitative RT-PCR, ERK phosphorylation assay, apoptosis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy, siRNA knockdown with downstream signaling readout, multiple orthogonal methods in single study","pmids":["17726105"],"is_preprint":false},{"year":2013,"finding":"EphA7 interacts with death receptor TNFR1 to form a multi-protein complex upon ephrinA5 stimulation; pull-down with biotinylated ephrinA5-Fc confirmed ephrinA5-EphA7 complexes recruit TNFR1; both the internalization motif and death domain of TNFR1 are required for interaction with the intracytoplasmic region of EphA7; this complex is essential for caspase-dependent apoptotic cell death.","method":"Pull-down assay with biotinylated ephrinA5-Fc, co-immunoprecipitation, immunocytochemistry, domain deletion mutants","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of multi-protein complex with domain mutagenesis and functional apoptosis readout, single lab with multiple orthogonal methods","pmids":["23657875"],"is_preprint":false},{"year":2014,"finding":"EphA7 signaling in cortical neurons restricts dendritic extent (via Src and Tsc1 as downstream mediators) and later promotes dendritic spine maturation and synaptic function; EphA7-/- neurons have longer, more complex dendrites, while EphA7 overexpression shortens dendrites; electrophysiological maturation of pyramidal neurons is delayed in EphA7-null cultures.","method":"Patterned substrates, EphA7 knockout mice, in vitro overexpression, electrophysiology, in vivo perturbation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — EphA7 KO with in vitro and in vivo phenotypes, identification of downstream mediators (Src, Tsc1), electrophysiology, multiple orthogonal methods","pmids":["24707048"],"is_preprint":false},{"year":2014,"finding":"EphA4 and EphA7 are expressed in the pericloacal mesenchyme and are required for nephric duct insertion into the cloaca; Epha4-/-;Epha7+/- and double knockout mice show distal ureter malformations and failure of ND-cloaca fusion; conditional deletion of ephrin-B2 from the nephric duct phenocopies this, indicating that EphA4/EphA7 from pericloacal mesenchyme signal via ephrin-B2 to mediate ND insertion.","method":"Compound knockout mice, conditional ephrin-B2 deletion, embryo analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with compound knockouts and conditional ligand deletion establishing signaling directionality, clear phenotypic readout","pmids":["25139858"],"is_preprint":false},{"year":2016,"finding":"EphA7 receptor tyrosine kinase is required for stabilization of basket cell inhibitory synaptic terminals on proximal dendritic and somatic compartments of dentate gyrus granule cells; EphA7 deficiency destabilizes GABAergic synapses and impairs LTP and hippocampal learning; EphA7 overexpression or ephrin stimulation induces gephyrin clustering in an mTOR-dependent manner, and activated mTOR releases its interaction with gephyrin while enhancing gephyrin-collybistin interaction.","method":"Lentiviral knockdown in adult rats, electrophysiology (LTP), behavior, gephyrin clustering assay, co-immunoprecipitation (gephyrin-mTOR, gephyrin-collybistin)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with behavioral and electrophysiological readouts plus biochemical pathway dissection (mTOR-gephyrin-collybistin), multiple orthogonal methods","pmids":["27405707"],"is_preprint":false},{"year":2016,"finding":"EphA7 forward signaling via ephrinA5 in human hematopoietic stem and progenitor cells (HSPCs) promotes colony formation, adhesion, and migration through Rac1 activation and upregulation of WAVE1; blocking EphA7 activation reduces HSPC adhesion and migration; Rac1 inhibition abolishes ephrinA5-mediated HSPC adhesion and migration.","method":"EphrinA5-Fc stimulation, functional blocking peptides, long-term culture-initiating cell assays, adhesion/migration assays, Rac1 inhibitor, gene/protein expression analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with ligand stimulation and blocking reagents identifying Rac1 as downstream mediator, single lab","pmids":["27988259"],"is_preprint":false},{"year":2017,"finding":"Ligand-dependent EphA7 signaling suppresses prostate cancer tumor growth and induces apoptosis via increased Bax, elevated caspase-3 activity, reduced Bcl-2, and dephosphorylation of Akt (PI3K/Akt pathway); EphA7 variants lacking the cytoplasmic domain or with a phosphorylation-inhibiting point mutation have no tumor suppressive effect in vivo or in vitro, demonstrating that receptor phosphorylation is essential.","method":"Site-directed mutagenesis, overexpression in PCa cells, in vivo tumor xenograft, apoptosis assays, western blotting for Bax/Bcl-2/Akt phosphorylation","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of phosphorylation site with in vitro and in vivo functional readouts and downstream signaling analysis, single lab with multiple orthogonal methods","pmids":["29022918"],"is_preprint":false},{"year":2019,"finding":"Endogenously expressed EphA7 in BJAB B cells functions as a receptor for KSHV gH/gL glycoprotein complex and is critical for cell-to-cell transmission of KSHV; endogenous EphA7 was precipitated from BJAB cell lysate using recombinant gH/gL; EphA7 knockout significantly reduced KSHV transmission; EphA7 also functions as receptor for cell-free infection by rhesus monkey rhadinovirus.","method":"Protein precipitation with recombinant gH/gL, CRISPR/Cas9 knockout, viral infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical binding confirmed by pulldown, functional consequence validated by CRISPR knockout, multiple viral infection assays","pmids":["31118261"],"is_preprint":false},{"year":2019,"finding":"Zfp422 transcription factor directly binds a 169-bp upstream enhancer region of EphA7 (identified by ChIP-Seq) and regulates EphA7 expression; EphA7 expression maintains proper myoblast apoptosis required for differentiation; knockdown of EphA7 or deletion of Zfp422 inhibits myoblast apoptosis and impairs skeletal muscle differentiation and fusion.","method":"ChIP-Seq, Zfp422 conditional knockout in skeletal muscle, EphA7 siRNA knockdown, C2C12 differentiation assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-Seq identifies direct transcriptional regulation, in vivo KO plus in vitro KD with clear apoptosis/differentiation readout, single lab with multiple orthogonal methods","pmids":["31685980"],"is_preprint":false},{"year":2020,"finding":"EphA7 is expressed on terminally differentiated myocytes during embryonic/fetal myogenesis and nascent myofibers during regeneration; EphA7-/- mice have fewer, smaller myofibers at birth with fewer myonuclei; EphA7 promotes commitment of adjacent myoblasts to terminal differentiation via juxtacrine (cell-cell contact) signaling; exogenous EphA7 extracellular domain rescues the null phenotype in vitro.","method":"EphA7-/- mouse analysis, exogenous EphA7-ECD treatment, in vitro differentiation assays, in vivo muscle analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with in vivo developmental phenotype, in vitro rescue with purified extracellular domain, multiple independent readouts","pmids":["32314958"],"is_preprint":false},{"year":2020,"finding":"EphA7 full-length (EphA7-FL) and truncated isoform (EphA7-T1, lacking kinase domain) have opposing effects on cortical dendrite development: EphA7-FL inhibits dendritic growth and spine formation, while EphA7-T1 increases spine density; downstream signaling shifts with development (mTOR-dependent early, mTOR-independent late); EphA7-FL and EphA7-T1 directly interact in cultured cells, reducing EphA7-FL phosphorylation.","method":"Isoform overexpression in cultured neurons, in vivo rapamycin treatment, co-immunoprecipitation of isoforms, dendritic morphometry","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct isoform interaction demonstrated by co-IP, functional divergence confirmed by overexpression studies, in vivo pharmacological epistasis, single lab with multiple orthogonal methods","pmids":["33275600"],"is_preprint":false},{"year":2016,"finding":"Physical interaction between kinase-deficient EPHA10 and kinase-sufficient EPHA7 was demonstrated by co-immunoprecipitation; both receptors co-localize on the cell surface and exist as a complex in the cytoplasm and nucleus; expression of EPHB6 in MDA-MB-231 cells alters the co-localization pattern, abolishing nuclear co-localization.","method":"Co-immunoprecipitation, immunocytochemistry, stable EPHB6 transfection","journal":"Cancer genomics & proteomics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — co-IP demonstrates physical interaction but single lab, single method for the primary interaction; localization without full functional validation","pmids":["27566654"],"is_preprint":false},{"year":2015,"finding":"EphA7 is required for normal spiral ganglion neuron (SGN) innervation of cochlear hair cells; EphA7 deletion reduces inner radial bundles, ribbon synapses on inner hair cells, and overall auditory nerve activity; knockdown of EphA7 in SGNs diminishes SGN fiber outgrowth in vitro; ERK1/2 inhibition or Prkg1 knockout also reduces SGN fibers, placing ERK1/2 downstream of EphA7 signaling.","method":"EphA7 knockout mice, siRNA knockdown in SGN cultures, ERK inhibitors, Prkg1 knockout, immunohistochemistry, electrophysiology","journal":"Developmental neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple phenotypic readouts, in vitro KD, pharmacological and genetic epistasis identifying ERK1/2 as downstream effector","pmids":["26178595"],"is_preprint":false},{"year":2007,"finding":"HOXA13 directly binds cis-regulatory elements in the EphA6 and EphA7 promoters in vivo (GT chromatin immunoprecipitation); HOXA13 activates EphA7 gene expression through these regulatory elements in vitro; Hoxa13-/- mice show reduced EphA7 expression in the genital tubercle vascular endothelia.","method":"ChIP from genital tubercle tissue, in vitro transcriptional activation assays, Hoxa13 mutant mice","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo ChIP combined with in vitro luciferase assay and genetic knockout, multiple orthogonal methods","pmids":["17304517"],"is_preprint":false},{"year":2016,"finding":"BMI-1 (encoded by BMI1) directly targets EphA7 in neural cells and lymphocytes, repressing it via H3K27 trimethylation and DNA methylation; BMI-1 overexpression is identified as a novel mechanism leading to EphA7 inactivation.","method":"ChIP (implied by chromatin modification analysis), BMI-1 overexpression, expression analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — chromatin modification and BMI-1 overexpression data identify EphA7 as direct target, but abstract lacks detail on specific methods; single lab","pmids":["27533460"],"is_preprint":false},{"year":2022,"finding":"Satb2 transcription factor directly suppresses EphA7 expression in cortical neurons (ChIP and luciferase reporter assays); Satb2 conditional knockout increases EphA7 in layers II/III; overexpression of EphA7 in wild-type neurons phenocopies Satb2 knockdown (soma clumping, impaired dendritic self-avoidance); reducing EphA7 rescues Satb2-knockdown phenotypes.","method":"ChIP, luciferase reporter assay, RNA-seq, in utero electroporation (overexpression and rescue), Satb2 conditional KO mice","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct transcriptional suppression demonstrated by ChIP and luciferase assay, genetic epistasis confirmed by rescue experiment, single lab with multiple orthogonal methods","pmids":["34546353"],"is_preprint":false},{"year":2016,"finding":"EphA4 and EphA7 interact differently with ligands in the developing neocortex and thalamus: EphA7 (but not EphA4) shows strong interaction with ligands in somatosensory thalamic nuclei; EphA7 affects both cortical neuronal migration and CT axon guidance, while EphA4 affects only cortical neuronal migration, demonstrating functional specificity between closely related Eph receptors.","method":"Ligand binding assays, EphA4 and EphA7 mutant mouse analysis, cortical axon tracing","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative binding and in vivo KO analysis, clear functional dissociation between paralogs, single lab","pmids":["26587807"],"is_preprint":false},{"year":2017,"finding":"EphA7 is specifically expressed in Xenopus pronephric tubules; EphA7 knockdown causes tubule cell differentiation and morphogenesis defects; EphA7 binds and phosphorylates claudin6 (CLDN6) in cultured cells, reducing CLDN6 distribution at the cell surface; a secreted (soluble) form of EphA7 (sEphA7) antagonizes full-length EphA7.","method":"Morpholino knockdown in Xenopus, co-immunoprecipitation, phosphorylation assay in cultured cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction (binding + phosphorylation of CLDN6) combined with in vivo morpholino phenotype, single lab with two orthogonal methods","pmids":["29223398"],"is_preprint":false},{"year":2016,"finding":"EphA7 knockdown in Xenopus hindbrain disrupts cranial neural tube closure and inhibits apical constriction of neuroepithelial cells, leading to reduced apical F-actin accumulation; EphA7 mediates phosphorylation/activation of focal adhesion kinase (FAK) in vivo and in vitro.","method":"Morpholino knockdown in Xenopus, phalloidin staining for F-actin, FAK phosphorylation assay in vivo and in vitro","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with in vivo and in vitro FAK phosphorylation readout, single lab with orthogonal methods","pmids":["27693790"],"is_preprint":false},{"year":2020,"finding":"Nicalin (a Nicastrin-like protein) interacts with soluble EphA7 (sEphA7) and they co-localize in the endoplasmic reticulum; Nicalin reduces the membranous level of sEphA7 while increasing insoluble cytoplasmic forms with reduced molecular weight, restricting sEphA7 entry into the ER for further modification; sEphA7 enhances EphA7-FL membrane levels and EphA7 complex formation, effects reversed by Nicalin.","method":"Immunoprecipitation/mass spectrometry, co-localization, subcellular fractionation, co-immunoprecipitation in HEK293 cells","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — IP/MS identification of interacting protein validated by co-IP and co-localization, functional consequence described, single lab","pmids":["32914261"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of EphA7 kinase domain mutants Gly656Arg, Gly656Glu, and Asp751His reveal structural changes in the hinge region and nucleotide-binding groove; Gly656Arg and Asp751His show secondary structural changes affecting open/closed kinase conformation transitions; Asp751His shows a distorted nucleotide-binding groove; differences in hydrogen bonding and hydrophobic interactions in the DFG motif suggest these mutations influence catalytic activity.","method":"X-ray crystallography of kinase domain mutants","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Weak — crystal structures provide direct structural evidence, but functional catalytic activity not directly measured in this study; structural inferences about DFG motif","pmids":["34186436"],"is_preprint":false},{"year":2023,"finding":"STAT3 transcriptionally activates EphA7 expression in ESCC cells; ChIP assay identified the -2000 to -1500 region as the key EphA7 promoter bound by STAT3; STAT3 inhibition (Stattic) reduces EphA7 protein expression while IL-6-mediated STAT3 activation upregulates it; EphA7 is required for STAT3 activation-driven cell proliferation of ESCC.","method":"ChIP assay, truncated promoter/luciferase assay, STAT3 inhibitor treatment, IL-6 stimulation, siRNA knockdown, RNA-seq","journal":"Acta oncologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies direct promoter binding with luciferase reporter confirmation, pharmacological and genetic modulation with functional readout, single lab","pmids":["37738252"],"is_preprint":false},{"year":2025,"finding":"METTL3 (the N6-adenosine-methyltransferase catalytic subunit) stabilizes EPHA7 expression through an m6A-dependent mechanism; chidamide downregulates METTL3, thereby reducing EPHA7; overexpression of EPHA7 counteracts METTL3 silencing effects, placing EPHA7 downstream of METTL3 in the same axis.","method":"METTL3 overexpression/silencing, EPHA7 overexpression rescue, in vivo xenograft, western blotting","journal":"Journal of chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis (overexpression rescue) with in vivo validation identifies post-transcriptional regulation by m6A, single lab, mechanism of m6A effect on EPHA7 not directly biochemically confirmed in abstract","pmids":["40586624"],"is_preprint":false},{"year":2025,"finding":"tRFAla-AGC-3-M8 (a tRNA-derived small RNA) directly targets EphA7 mRNA (validated by dual-luciferase reporter assay); in Alzheimer's disease (APP/PS1 mice), EphA7 is upregulated in microglia and neurons, with increased ERK1/2 and p70S6K phosphorylation; EphA7 siRNA knockdown suppresses ERK1/2-p70S6K signaling, reduces tau hyperphosphorylation in neurons, and reduces M1-type polarization of microglia.","method":"Dual-luciferase reporter assay, siRNA knockdown, western blotting, immunofluorescence, APP/PS1 transgenic mice","journal":"Alzheimer's research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay, in vitro and in vivo functional dissection of EphA7-ERK1/2-p70S6K pathway, single lab with multiple methods","pmids":["40375351"],"is_preprint":false},{"year":2025,"finding":"In cervical cancer, SP1 and MAZ bind the EphA7 promoter (identified by CRISPR-mediated pull-down); EphA7 expression is regulated by SP1/DNMT1 (but not MAZ); 17-β-estradiol (E2) upregulates EphA7 expression through demethylation via the SP1/DNMT1 axis; CRISPR-based demethylation (dCas9-Tet1) reactivates EphA7 and suppresses tumor proliferation/invasion via PI3K/AKT signaling.","method":"CRISPR-mediated promoter pull-down, SP1/DNMT1 perturbation, dCas9-Tet1 demethylation, luciferase assay, western blotting for PI3K/AKT","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel CRISPR pull-down identifies upstream regulators, functional rescue by targeted demethylation with pathway readout, single lab","pmids":["40258813"],"is_preprint":false},{"year":2019,"finding":"EphA7+ pericytes (CapSCs) isolated from mouse microvasculature are multipotent cells distinct from EphA7- control pericytes; EphA7 identifies a subpopulation with high multipotency, differentiating into mesenchymal, neuronal, endothelial, and pericyte lineages; transplantation of CapSCs into ischemic tissues improves blood flow recovery and vascular formation.","method":"FACS isolation, microarray identification of EphA7 as marker, in vitro multipotency assays, in vivo transplantation in hindlimb ischemia model","journal":"Stem cells translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FACS-based isolation and functional validation of EphA7 as pericyte subpopulation marker, in vivo transplantation with functional readout, single lab","pmids":["31471947"],"is_preprint":false},{"year":2024,"finding":"In human rhabdomyosarcoma (hRMS) cells, EphA7 binds and signals through ephrin-A2 (rather than ephrin-A5 as in normal muscle), and both EphA7-Fc and ephrin-A5-Fc are potent inhibitors of hRMS proliferation in vitro.","method":"Binding assays, Fc-chimera proliferation assays, expression profiling of Eph/ephrin in hRMS vs. normal muscle","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — binding and functional proliferation assays identify divergent receptor-ligand specificity in hRMS, single lab","pmids":["40426233"],"is_preprint":false}],"current_model":"EphA7 is a receptor tyrosine kinase that produces full-length (TK+) and truncated/soluble kinase-domain-lacking isoforms with opposing functions: the TK+ isoform mediates repulsive ephrin-A signaling to guide corticothalamic axon topography, restrict dendritic growth, and regulate cortical domain formation, while the TK- isoform acts as a dominant-negative modulator and can enhance dendritic spine density; ligand-dependent phosphorylation of EphA7 is essential for its tumor-suppressive functions (via PI3K/Akt dephosphorylation, Bax/caspase-3/Bcl-2 modulation) and its pro-differentiation role in skeletal muscle; EphA7 also forms multi-protein complexes with TNFR1 upon ephrinA5 stimulation to induce caspase-dependent apoptosis, regulates inhibitory synaptic connectivity via mTOR-gephyrin-collybistin signaling, promotes HSPC maintenance via Rac1 activation, and is transcriptionally controlled by multiple regulators including HOXA13/HOXD13, STAT3, BMI-1 (via H3K27me3), and methylation of its promoter CpG island."},"narrative":{"mechanistic_narrative":"EPHA7 is an ephrin-A receptor tyrosine kinase that guides topographic axon and tissue patterning during development and acts as a context-dependent regulator of cell survival and differentiation [PMID:16301174, PMID:16615124, PMID:32314958]. The gene produces a full-length kinase-active isoform (TK+) and a truncated isoform lacking the kinase domain (TK-) that are distributed in distinct neuronal compartments and exert opposing actions: the kinase-active isoform mediates repulsive ephrin-A signaling to control corticothalamic projection topography, restrict dendritic growth, and regulate cortical domain formation, whereas the truncated isoform dimerizes with and dampens phosphorylation of the full-length receptor, behaving as a dominant-negative modulator that can instead increase dendritic spine density [PMID:16615124, PMID:10640696, PMID:33275600]. EphA7 signaling restricts dendritic extent through Src and Tsc1 and stabilizes GABAergic inhibitory synaptic terminals through an mTOR–gephyrin–collybistin axis essential for hippocampal LTP and learning [PMID:24707048, PMID:27405707]. In peripheral tissues EphA7 directs nephric duct insertion via ephrin-B2, spiral ganglion neuron innervation of cochlear hair cells through ERK1/2, and skeletal muscle differentiation by promoting myoblast apoptosis and terminal commitment through juxtacrine contact [PMID:25139858, PMID:26178595, PMID:32314958]. Ligand-dependent receptor phosphorylation underlies a tumor-suppressive function in which EphA7 induces apoptosis via Bax/caspase-3/Bcl-2 modulation and dephosphorylation of Akt, and a kinase-dead or cytoplasmic-domain-deleted receptor loses this activity [PMID:29022918]. Beyond its kinase signaling, EphA7 forms a death-inducing complex with TNFR1 upon ephrinA5 stimulation to trigger caspase-dependent apoptosis, and serves as a cell-surface receptor for KSHV gH/gL-mediated viral entry and transmission [PMID:23657875, PMID:31118261]. EphA7 transcription is tightly controlled by HOXA13/HOXD13, STAT3, SP1/DNMT1, and Satb2, and is silenced by BMI-1-directed H3K27 trimethylation and promoter CpG methylation [PMID:16314414, PMID:17304517, PMID:37738252, PMID:34546353, PMID:27533460, PMID:40258813].","teleology":[{"year":1999,"claim":"Established that EphA7 is expressed as two functionally distinct isoforms with separate subcellular distributions, framing the gene as more than a single repulsive receptor.","evidence":"Isoform-specific antibody immunohistochemistry in adult mouse brain","pmids":["10640696"],"confidence":"Medium","gaps":["No functional rescue distinguishing isoform roles in this study","Dominant-negative model inferred from localization, not tested biochemically"]},{"year":2005,"claim":"Demonstrated that EphA7 on cortical axons sets corticothalamic projection topography, defining its developmental axon-guidance role in vivo.","evidence":"In utero electroporation mis-expression and axon tracing in mouse cortex","pmids":["16301174"],"confidence":"High","gaps":["Ligand and downstream effectors of the topographic signal not identified here","Gain-of-function only"]},{"year":2005,"claim":"Identified EphA7 as a direct transcriptional target of paralog-group-13 Hox proteins, linking limb patterning programs to its expression.","evidence":"In vivo ChIP, promoter reporter, and binding-site mutagenesis in mouse limb","pmids":["16314414"],"confidence":"High","gaps":["Functional consequence of Hox-driven EphA7 in limb morphogenesis not dissected"]},{"year":2006,"claim":"Showed that the TK+/TK- isoform ratio shifts across cortical development and that EphA7 controls ephrin-A5 distribution and cortical area size, establishing it as a regulator of cortical domain formation.","evidence":"EphA7-/- mouse analysis with isoform expression profiling and cortical area measurements","pmids":["16615124"],"confidence":"High","gaps":["Mechanism by which isoform ratio is regulated unknown","Direct measurement of repulsive signaling strength absent"]},{"year":2007,"claim":"Extended Hox control to genital tubercle vasculature and revealed leukemogenic fusion proteins can hijack the EphA7 promoter, showing context-specific transcriptional regulation tied to ERK signaling.","evidence":"ChIP, transcriptional activation assays, Hoxa13 mutant mice, and ALL1-fusion knockdown with ERK/apoptosis readouts","pmids":["17304517","17726105"],"confidence":"High","gaps":["Whether EphA7 kinase activity drives ERK in leukemic cells not resolved","Direct vs indirect ERK coupling unclear"]},{"year":2013,"claim":"Revealed a kinase-independent death pathway in which ephrinA5-bound EphA7 recruits TNFR1 to drive caspase-dependent apoptosis.","evidence":"EphrinA5-Fc pull-down, co-IP, and TNFR1 domain-deletion mutants with apoptosis assays","pmids":["23657875"],"confidence":"High","gaps":["Physiological setting of the EphA7-TNFR1 complex not defined","Stoichiometry of the multiprotein complex unknown"]},{"year":2014,"claim":"Defined the downstream effectors (Src, Tsc1) by which EphA7 restricts dendrite growth and later promotes spine maturation, and showed EphA7/EphA4 from pericloacal mesenchyme signal via ephrin-B2 for nephric duct insertion.","evidence":"EphA7 KO with patterned substrates, electrophysiology, and compound/conditional knockout genetics","pmids":["24707048","25139858"],"confidence":"High","gaps":["How a single receptor switches from growth-restricting to spine-maturing not mechanistically resolved","Direct biochemical link to ephrin-B2 reverse signaling inferred genetically"]},{"year":2015,"claim":"Placed EphA7 upstream of ERK1/2 in spiral ganglion neuron innervation, generalizing its role in directed neuronal connectivity to the auditory system.","evidence":"EphA7 KO mice, SGN culture knockdown, ERK inhibitors, and Prkg1 knockout with electrophysiology","pmids":["26178595"],"confidence":"High","gaps":["Ligand identity for SGN signaling not specified","Coupling of EphA7 to ERK1/2 mechanistically indirect"]},{"year":2016,"claim":"Connected EphA7 to inhibitory synapse stability through an mTOR-gephyrin-collybistin axis, to HSPC adhesion/migration via Rac1, and revealed paralog-specific functions versus EphA4.","evidence":"In vivo knockdown with LTP/behavior, gephyrin co-IPs, ephrinA5-Fc HSPC assays with Rac1 inhibition, and comparative ligand-binding KO analysis","pmids":["27405707","27988259","26587807"],"confidence":"High","gaps":["How EphA7 activation engages mTOR not biochemically traced","HSPC findings are Medium-confidence single-lab"]},{"year":2016,"claim":"Identified BMI-1 epigenetic silencing and an EPHA10 heterocomplex, broadening regulatory inputs and receptor-receptor interactions.","evidence":"BMI-1 overexpression with chromatin-modification analysis and EPHA7-EPHA10 co-IP/co-localization","pmids":["27533460","27566654"],"confidence":"Medium","gaps":["BMI-1 study lacks detailed method reporting","EPHA10 interaction is single-lab co-IP without functional readout"]},{"year":2017,"claim":"Established that ligand-dependent receptor phosphorylation is required for EphA7 tumor suppression via PI3K/Akt dephosphorylation and Bax/caspase-3/Bcl-2 modulation, and identified CLDN6 as a substrate in renal tubule morphogenesis.","evidence":"Phospho-site mutagenesis with xenograft/apoptosis assays in prostate cancer; Xenopus morpholino with CLDN6 binding and phosphorylation assays","pmids":["29022918","29223398"],"confidence":"High","gaps":["Direct kinase substrates linking phosphorylation to Akt dephosphorylation unknown","CLDN6 work is Medium-confidence single-lab"]},{"year":2019,"claim":"Showed EphA7 is a functional receptor for KSHV gH/gL viral entry, defined Zfp422 enhancer control of EphA7-driven myoblast apoptosis, and identified EphA7 as a multipotent pericyte marker.","evidence":"Recombinant gH/gL precipitation with CRISPR KO infection assays; ChIP-Seq with Zfp422 KO and C2C12 differentiation; FACS isolation and ischemia transplantation","pmids":["31118261","31685980","31471947"],"confidence":"High","gaps":["Whether viral receptor function requires kinase activity untested","Pericyte marker role is Medium-confidence correlative isolation"]},{"year":2020,"claim":"Demonstrated EphA7 drives skeletal muscle terminal differentiation by juxtacrine signaling and confirmed full-length and truncated isoforms physically interact to oppose each other in cortical dendrite development.","evidence":"EphA7 KO mice with ECD rescue and muscle analysis; isoform overexpression, co-IP, and in vivo rapamycin epistasis; Nicalin IP/MS and fractionation","pmids":["32314958","33275600","32914261"],"confidence":"High","gaps":["mTOR-dependence switch across development not biochemically mapped","Nicalin/sEphA7 ER trafficking role is Medium-confidence single-lab"]},{"year":2021,"claim":"Provided structural insight into how kinase-domain mutations alter hinge, DFG motif, and nucleotide-binding conformations relevant to catalytic regulation.","evidence":"X-ray crystallography of EphA7 kinase-domain point mutants","pmids":["34186436"],"confidence":"High","gaps":["Catalytic activity of mutants not directly measured","Functional consequence in cells not tested"]},{"year":2023,"claim":"Defined STAT3 as a direct activator of EphA7 required for STAT3-driven proliferation in esophageal squamous cell carcinoma, contrasting with its tumor-suppressive role elsewhere.","evidence":"ChIP, truncated-promoter luciferase, STAT3 inhibition, IL-6 stimulation, and siRNA with RNA-seq","pmids":["37738252"],"confidence":"Medium","gaps":["Why EphA7 is pro-proliferative in ESCC versus suppressive in prostate not reconciled","Single-lab"]},{"year":2025,"claim":"Expanded the regulatory and effector network with m6A stabilization by METTL3, a tRNA-derived fragment targeting EphA7 mRNA in Alzheimer's models, SP1/DNMT1 demethylation control, and divergent ephrin-A2 usage in rhabdomyosarcoma.","evidence":"METTL3 epistasis with xenograft; dual-luciferase tRF targeting with ERK1/2-p70S6K dissection in APP/PS1 mice; CRISPR promoter pull-down with dCas9-Tet1 demethylation; Fc-chimera binding/proliferation assays in hRMS","pmids":["40586624","40375351","40258813","40426233"],"confidence":"Medium","gaps":["Biochemical site of m6A on EPHA7 not confirmed","Ligand-specificity switch mechanism in tumors unresolved","All single-lab Medium-confidence"]},{"year":null,"claim":"How a single receptor reconciles opposing tumor-suppressive (Akt dephosphorylation, apoptosis) and tumor-promoting (STAT3-driven proliferation) outcomes, and how isoform ratio, ligand identity, and phosphorylation state are coordinated to select among repulsion, apoptosis, differentiation, and viral entry, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phosphorylation-dependent and kinase-independent functions","Context-determinants of pro- vs 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cortical dendrite development.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33275600","citation_count":9,"is_preprint":false},{"pmid":"34176129","id":"PMC_34176129","title":"EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder.","date":"2021","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34176129","citation_count":9,"is_preprint":false},{"pmid":"16844303","id":"PMC_16844303","title":"EphA7 receptor is expressed differentially at chicken prosomeric boundaries.","date":"2006","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16844303","citation_count":9,"is_preprint":false},{"pmid":"26587807","id":"PMC_26587807","title":"EphA4 has distinct functionality from EphA7 in the corticothalamic system during mouse brain development.","date":"2015","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26587807","citation_count":9,"is_preprint":false},{"pmid":"34546353","id":"PMC_34546353","title":"Satb2 Regulates EphA7 to Control Soma Spacing and Self-Avoidance of Cortical Pyramidal Neurons.","date":"2022","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/34546353","citation_count":8,"is_preprint":false},{"pmid":"25009468","id":"PMC_25009468","title":"Complementary expression of EphA7 and SCO-spondin during posterior commissure development.","date":"2014","source":"Frontiers in neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/25009468","citation_count":8,"is_preprint":false},{"pmid":"23321235","id":"PMC_23321235","title":"Increased expression of EphA7 in inflamed human dental pulp.","date":"2013","source":"Journal of endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/23321235","citation_count":8,"is_preprint":false},{"pmid":"27533460","id":"PMC_27533460","title":"The putative tumor suppressor gene EphA7 is a novel BMI-1 target.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27533460","citation_count":8,"is_preprint":false},{"pmid":"32738632","id":"PMC_32738632","title":"EphA7+ perivascular cells as myogenic and angiogenic precursors improving skeletal muscle regeneration in a muscular dystrophic mouse model.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32738632","citation_count":8,"is_preprint":false},{"pmid":"22356769","id":"PMC_22356769","title":"Mining the cancer genome uncovers therapeutic activity of EphA7 against lymphoma.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22356769","citation_count":8,"is_preprint":false},{"pmid":"40258813","id":"PMC_40258813","title":"Targeted demethylation of the EphA7 promoter inhibits tumorigenesis via the SP1/DNMT1 and PI3K/AKT axes and improves the response to multiple therapies in cervical cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40258813","citation_count":7,"is_preprint":false},{"pmid":"20302756","id":"PMC_20302756","title":"[Expression of EphA7 protein in primary hepatocellular carcinoma and its clinical significance].","date":"2010","source":"Zhonghua wai ke za zhi [Chinese journal of surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/20302756","citation_count":7,"is_preprint":false},{"pmid":"22246354","id":"PMC_22246354","title":"[Expression of EphA7 and MTDH and clinicopathological significance in the squamous cell cancer of the tongue].","date":"2011","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22246354","citation_count":6,"is_preprint":false},{"pmid":"29223398","id":"PMC_29223398","title":"EphA7 regulates claudin6 and pronephros development in Xenopus.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29223398","citation_count":5,"is_preprint":false},{"pmid":"35103233","id":"PMC_35103233","title":"Loss of EphA7 Expression in Basal Cell Carcinoma by Hypermethylation of CpG Islands in the Promoter Region.","date":"2022","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/35103233","citation_count":5,"is_preprint":false},{"pmid":"27693790","id":"PMC_27693790","title":"EphA7 modulates apical constriction of hindbrain neuroepithelium during neurulation in Xenopus.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27693790","citation_count":5,"is_preprint":false},{"pmid":"39329983","id":"PMC_39329983","title":"The Role of Biomarkers in the Early Diagnosis of Gastric Cancer: A Study on CCR5, CCL5, PDGF, and EphA7.","date":"2024","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39329983","citation_count":5,"is_preprint":false},{"pmid":"21345310","id":"PMC_21345310","title":"Identification of EphA7 BAC clone containing a long-range dorsal midline-specific enhancer.","date":"2011","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/21345310","citation_count":4,"is_preprint":false},{"pmid":"37738252","id":"PMC_37738252","title":"STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma.","date":"2023","source":"Acta oncologica (Stockholm, Sweden)","url":"https://pubmed.ncbi.nlm.nih.gov/37738252","citation_count":3,"is_preprint":false},{"pmid":"32222280","id":"PMC_32222280","title":"EphA7 is required for otic epithelial homeostasis by modulating Claudin6 in Xenopus.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32222280","citation_count":3,"is_preprint":false},{"pmid":"34186436","id":"PMC_34186436","title":"Crystal structure of clinically reported mutations Gly656Arg, Gly656Glu and Asp751His identified in the kinase domain of EphA7.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34186436","citation_count":2,"is_preprint":false},{"pmid":"39763772","id":"PMC_39763772","title":"Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39763772","citation_count":1,"is_preprint":false},{"pmid":"26780036","id":"PMC_26780036","title":"Regional expression and ultrastructural localization of EphA7 in the hippocampus and cerebellum of adult rat.","date":"2016","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26780036","citation_count":1,"is_preprint":false},{"pmid":"40530558","id":"PMC_40530558","title":"Knockdown of miR-204-5p promotes nerve regeneration and functional recovery after hypoxic-ischemic brain damage in neonatal rats via the Wnt2/Ephrin-A2/EphA7 pathway.","date":"2025","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/40530558","citation_count":1,"is_preprint":false},{"pmid":"26537192","id":"PMC_26537192","title":"Identification of the 187 bp EphA7 Genomic DNA as the Dorsal Midline-Specific Enhancer of the Diencephalon and Mesencephalon.","date":"2015","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/26537192","citation_count":1,"is_preprint":false},{"pmid":"40426233","id":"PMC_40426233","title":"Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro.","date":"2025","source":"Skeletal muscle","url":"https://pubmed.ncbi.nlm.nih.gov/40426233","citation_count":0,"is_preprint":false},{"pmid":"32914261","id":"PMC_32914261","title":"Identification of the soluble EphA7-interacting protein Nicalin as a regulator of EphA7 expression.","date":"2020","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32914261","citation_count":0,"is_preprint":false},{"pmid":"41307306","id":"PMC_41307306","title":"Comprehensive analysis of Ephrin ligand and receptor expression reveals exclusive domains during nephrogenesis for epha4/epha7 and efna3.","date":"2025","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41307306","citation_count":0,"is_preprint":false},{"pmid":"40586624","id":"PMC_40586624","title":"Chidamide impedes the progression of non-small cell lung cancer by inhibiting the METTL3/EPHA7 pathway.","date":"2025","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/40586624","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.23.629471","title":"Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma  <i>in vitro</i>","date":"2024-12-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.23.629471","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42980,"output_tokens":8498,"usd":0.128205,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18026,"output_tokens":5510,"usd":0.11394,"stage2_stop_reason":"end_turn"},"total_usd":0.242145,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"EphA7-mediated signaling on neocortical axons controls the within-nucleus topography of corticothalamic (CT) projections in the thalamus, as demonstrated by in utero electroporation-mediated mis-expression of EphA7 in cortical neurons, which disrupted CT topography without altering thalamocortical projection topography.\",\n      \"method\": \"In utero electroporation-mediated gene transfer, axon tracing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo gain-of-function with electroporation, specific phenotypic readout (CT vs TC topography dissociation), single lab but rigorous design\",\n      \"pmids\": [\"16301174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA13 and HOXD13 directly bind to cis-regulatory sites in the EphA7 promoter in vivo (ChIP in developing mouse limbs) and activate EphA7 transcription; mutation of the HOXA13/HOXD13 binding site abolishes activation, establishing EphA7 as a direct downstream target of paralog group 13 Hox proteins during limb development.\",\n      \"method\": \"ChIP in developing mouse limbs, promoter reporter assays, mutagenesis of binding sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo ChIP combined with promoter mutagenesis and luciferase assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16314414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EphA7 produces two isoforms from the same gene: a full-length receptor tyrosine kinase (TK+) and a truncated isoform lacking the kinase domain (TK-). The proportions of these isoforms shift during cortical development from a more repulsive (TK+ dominant) mix embryonically to a more permissive (TK- dominant) mix postnatally; in EphA7-/- mice, the distribution of ephrin-A5 is altered and the somatosensory cortex area is reduced, establishing EphA7 as a regulator of cortical domain formation and ephrin-A5 distribution.\",\n      \"method\": \"EphA7-/- mouse analysis, RNA expression profiling, in vivo functional studies, cortical area measurements\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple quantitative phenotypic readouts and isoform expression analysis, single lab with orthogonal methods\",\n      \"pmids\": [\"16615124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EphA7 encodes both a TK+ (full-length) and a TK- (kinase-domain-lacking) isoform with strikingly different distributions in adult mouse brain: TK+ immunoreactivity is on neuropil/axonal arborizations throughout telencephalon, while TK- is conspicuous on cell bodies and proximal dendrites of specific neuronal types; the TK- isoform may act as a dominant-negative antagonist to ensure TK+ responds only to signals at growing axon/dendrite tips.\",\n      \"method\": \"Isoform-specific antibodies, immunohistochemistry in adult mouse brain\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemical localization with isoform-specific antibodies, clear compartmentalization finding, single lab, no functional rescue experiment\",\n      \"pmids\": [\"10640696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ALL1/AF4 and ALL1/AF9 fusion proteins directly occupy the EphA7 promoter (ChIP) and transcriptionally upregulate EphA7 in leukemic cells; siRNA-mediated knockdown of ALL1/AF4 in t(4;11) cells downregulates EphA7; EphA7 upregulation is accompanied by ERK phosphorylation, and ERK inhibition induces apoptosis specifically in t(4;11) leukemic cells.\",\n      \"method\": \"ChIP, siRNA knockdown, quantitative RT-PCR, ERK phosphorylation assay, apoptosis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy, siRNA knockdown with downstream signaling readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17726105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EphA7 interacts with death receptor TNFR1 to form a multi-protein complex upon ephrinA5 stimulation; pull-down with biotinylated ephrinA5-Fc confirmed ephrinA5-EphA7 complexes recruit TNFR1; both the internalization motif and death domain of TNFR1 are required for interaction with the intracytoplasmic region of EphA7; this complex is essential for caspase-dependent apoptotic cell death.\",\n      \"method\": \"Pull-down assay with biotinylated ephrinA5-Fc, co-immunoprecipitation, immunocytochemistry, domain deletion mutants\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of multi-protein complex with domain mutagenesis and functional apoptosis readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23657875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EphA7 signaling in cortical neurons restricts dendritic extent (via Src and Tsc1 as downstream mediators) and later promotes dendritic spine maturation and synaptic function; EphA7-/- neurons have longer, more complex dendrites, while EphA7 overexpression shortens dendrites; electrophysiological maturation of pyramidal neurons is delayed in EphA7-null cultures.\",\n      \"method\": \"Patterned substrates, EphA7 knockout mice, in vitro overexpression, electrophysiology, in vivo perturbation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EphA7 KO with in vitro and in vivo phenotypes, identification of downstream mediators (Src, Tsc1), electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"24707048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EphA4 and EphA7 are expressed in the pericloacal mesenchyme and are required for nephric duct insertion into the cloaca; Epha4-/-;Epha7+/- and double knockout mice show distal ureter malformations and failure of ND-cloaca fusion; conditional deletion of ephrin-B2 from the nephric duct phenocopies this, indicating that EphA4/EphA7 from pericloacal mesenchyme signal via ephrin-B2 to mediate ND insertion.\",\n      \"method\": \"Compound knockout mice, conditional ephrin-B2 deletion, embryo analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with compound knockouts and conditional ligand deletion establishing signaling directionality, clear phenotypic readout\",\n      \"pmids\": [\"25139858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA7 receptor tyrosine kinase is required for stabilization of basket cell inhibitory synaptic terminals on proximal dendritic and somatic compartments of dentate gyrus granule cells; EphA7 deficiency destabilizes GABAergic synapses and impairs LTP and hippocampal learning; EphA7 overexpression or ephrin stimulation induces gephyrin clustering in an mTOR-dependent manner, and activated mTOR releases its interaction with gephyrin while enhancing gephyrin-collybistin interaction.\",\n      \"method\": \"Lentiviral knockdown in adult rats, electrophysiology (LTP), behavior, gephyrin clustering assay, co-immunoprecipitation (gephyrin-mTOR, gephyrin-collybistin)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with behavioral and electrophysiological readouts plus biochemical pathway dissection (mTOR-gephyrin-collybistin), multiple orthogonal methods\",\n      \"pmids\": [\"27405707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA7 forward signaling via ephrinA5 in human hematopoietic stem and progenitor cells (HSPCs) promotes colony formation, adhesion, and migration through Rac1 activation and upregulation of WAVE1; blocking EphA7 activation reduces HSPC adhesion and migration; Rac1 inhibition abolishes ephrinA5-mediated HSPC adhesion and migration.\",\n      \"method\": \"EphrinA5-Fc stimulation, functional blocking peptides, long-term culture-initiating cell assays, adhesion/migration assays, Rac1 inhibitor, gene/protein expression analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with ligand stimulation and blocking reagents identifying Rac1 as downstream mediator, single lab\",\n      \"pmids\": [\"27988259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ligand-dependent EphA7 signaling suppresses prostate cancer tumor growth and induces apoptosis via increased Bax, elevated caspase-3 activity, reduced Bcl-2, and dephosphorylation of Akt (PI3K/Akt pathway); EphA7 variants lacking the cytoplasmic domain or with a phosphorylation-inhibiting point mutation have no tumor suppressive effect in vivo or in vitro, demonstrating that receptor phosphorylation is essential.\",\n      \"method\": \"Site-directed mutagenesis, overexpression in PCa cells, in vivo tumor xenograft, apoptosis assays, western blotting for Bax/Bcl-2/Akt phosphorylation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of phosphorylation site with in vitro and in vivo functional readouts and downstream signaling analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29022918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endogenously expressed EphA7 in BJAB B cells functions as a receptor for KSHV gH/gL glycoprotein complex and is critical for cell-to-cell transmission of KSHV; endogenous EphA7 was precipitated from BJAB cell lysate using recombinant gH/gL; EphA7 knockout significantly reduced KSHV transmission; EphA7 also functions as receptor for cell-free infection by rhesus monkey rhadinovirus.\",\n      \"method\": \"Protein precipitation with recombinant gH/gL, CRISPR/Cas9 knockout, viral infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding confirmed by pulldown, functional consequence validated by CRISPR knockout, multiple viral infection assays\",\n      \"pmids\": [\"31118261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Zfp422 transcription factor directly binds a 169-bp upstream enhancer region of EphA7 (identified by ChIP-Seq) and regulates EphA7 expression; EphA7 expression maintains proper myoblast apoptosis required for differentiation; knockdown of EphA7 or deletion of Zfp422 inhibits myoblast apoptosis and impairs skeletal muscle differentiation and fusion.\",\n      \"method\": \"ChIP-Seq, Zfp422 conditional knockout in skeletal muscle, EphA7 siRNA knockdown, C2C12 differentiation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-Seq identifies direct transcriptional regulation, in vivo KO plus in vitro KD with clear apoptosis/differentiation readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31685980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA7 is expressed on terminally differentiated myocytes during embryonic/fetal myogenesis and nascent myofibers during regeneration; EphA7-/- mice have fewer, smaller myofibers at birth with fewer myonuclei; EphA7 promotes commitment of adjacent myoblasts to terminal differentiation via juxtacrine (cell-cell contact) signaling; exogenous EphA7 extracellular domain rescues the null phenotype in vitro.\",\n      \"method\": \"EphA7-/- mouse analysis, exogenous EphA7-ECD treatment, in vitro differentiation assays, in vivo muscle analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with in vivo developmental phenotype, in vitro rescue with purified extracellular domain, multiple independent readouts\",\n      \"pmids\": [\"32314958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA7 full-length (EphA7-FL) and truncated isoform (EphA7-T1, lacking kinase domain) have opposing effects on cortical dendrite development: EphA7-FL inhibits dendritic growth and spine formation, while EphA7-T1 increases spine density; downstream signaling shifts with development (mTOR-dependent early, mTOR-independent late); EphA7-FL and EphA7-T1 directly interact in cultured cells, reducing EphA7-FL phosphorylation.\",\n      \"method\": \"Isoform overexpression in cultured neurons, in vivo rapamycin treatment, co-immunoprecipitation of isoforms, dendritic morphometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct isoform interaction demonstrated by co-IP, functional divergence confirmed by overexpression studies, in vivo pharmacological epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33275600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Physical interaction between kinase-deficient EPHA10 and kinase-sufficient EPHA7 was demonstrated by co-immunoprecipitation; both receptors co-localize on the cell surface and exist as a complex in the cytoplasm and nucleus; expression of EPHB6 in MDA-MB-231 cells alters the co-localization pattern, abolishing nuclear co-localization.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, stable EPHB6 transfection\",\n      \"journal\": \"Cancer genomics & proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP demonstrates physical interaction but single lab, single method for the primary interaction; localization without full functional validation\",\n      \"pmids\": [\"27566654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EphA7 is required for normal spiral ganglion neuron (SGN) innervation of cochlear hair cells; EphA7 deletion reduces inner radial bundles, ribbon synapses on inner hair cells, and overall auditory nerve activity; knockdown of EphA7 in SGNs diminishes SGN fiber outgrowth in vitro; ERK1/2 inhibition or Prkg1 knockout also reduces SGN fibers, placing ERK1/2 downstream of EphA7 signaling.\",\n      \"method\": \"EphA7 knockout mice, siRNA knockdown in SGN cultures, ERK inhibitors, Prkg1 knockout, immunohistochemistry, electrophysiology\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple phenotypic readouts, in vitro KD, pharmacological and genetic epistasis identifying ERK1/2 as downstream effector\",\n      \"pmids\": [\"26178595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA13 directly binds cis-regulatory elements in the EphA6 and EphA7 promoters in vivo (GT chromatin immunoprecipitation); HOXA13 activates EphA7 gene expression through these regulatory elements in vitro; Hoxa13-/- mice show reduced EphA7 expression in the genital tubercle vascular endothelia.\",\n      \"method\": \"ChIP from genital tubercle tissue, in vitro transcriptional activation assays, Hoxa13 mutant mice\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo ChIP combined with in vitro luciferase assay and genetic knockout, multiple orthogonal methods\",\n      \"pmids\": [\"17304517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BMI-1 (encoded by BMI1) directly targets EphA7 in neural cells and lymphocytes, repressing it via H3K27 trimethylation and DNA methylation; BMI-1 overexpression is identified as a novel mechanism leading to EphA7 inactivation.\",\n      \"method\": \"ChIP (implied by chromatin modification analysis), BMI-1 overexpression, expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — chromatin modification and BMI-1 overexpression data identify EphA7 as direct target, but abstract lacks detail on specific methods; single lab\",\n      \"pmids\": [\"27533460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Satb2 transcription factor directly suppresses EphA7 expression in cortical neurons (ChIP and luciferase reporter assays); Satb2 conditional knockout increases EphA7 in layers II/III; overexpression of EphA7 in wild-type neurons phenocopies Satb2 knockdown (soma clumping, impaired dendritic self-avoidance); reducing EphA7 rescues Satb2-knockdown phenotypes.\",\n      \"method\": \"ChIP, luciferase reporter assay, RNA-seq, in utero electroporation (overexpression and rescue), Satb2 conditional KO mice\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional suppression demonstrated by ChIP and luciferase assay, genetic epistasis confirmed by rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34546353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA4 and EphA7 interact differently with ligands in the developing neocortex and thalamus: EphA7 (but not EphA4) shows strong interaction with ligands in somatosensory thalamic nuclei; EphA7 affects both cortical neuronal migration and CT axon guidance, while EphA4 affects only cortical neuronal migration, demonstrating functional specificity between closely related Eph receptors.\",\n      \"method\": \"Ligand binding assays, EphA4 and EphA7 mutant mouse analysis, cortical axon tracing\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative binding and in vivo KO analysis, clear functional dissociation between paralogs, single lab\",\n      \"pmids\": [\"26587807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EphA7 is specifically expressed in Xenopus pronephric tubules; EphA7 knockdown causes tubule cell differentiation and morphogenesis defects; EphA7 binds and phosphorylates claudin6 (CLDN6) in cultured cells, reducing CLDN6 distribution at the cell surface; a secreted (soluble) form of EphA7 (sEphA7) antagonizes full-length EphA7.\",\n      \"method\": \"Morpholino knockdown in Xenopus, co-immunoprecipitation, phosphorylation assay in cultured cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction (binding + phosphorylation of CLDN6) combined with in vivo morpholino phenotype, single lab with two orthogonal methods\",\n      \"pmids\": [\"29223398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA7 knockdown in Xenopus hindbrain disrupts cranial neural tube closure and inhibits apical constriction of neuroepithelial cells, leading to reduced apical F-actin accumulation; EphA7 mediates phosphorylation/activation of focal adhesion kinase (FAK) in vivo and in vitro.\",\n      \"method\": \"Morpholino knockdown in Xenopus, phalloidin staining for F-actin, FAK phosphorylation assay in vivo and in vitro\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with in vivo and in vitro FAK phosphorylation readout, single lab with orthogonal methods\",\n      \"pmids\": [\"27693790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nicalin (a Nicastrin-like protein) interacts with soluble EphA7 (sEphA7) and they co-localize in the endoplasmic reticulum; Nicalin reduces the membranous level of sEphA7 while increasing insoluble cytoplasmic forms with reduced molecular weight, restricting sEphA7 entry into the ER for further modification; sEphA7 enhances EphA7-FL membrane levels and EphA7 complex formation, effects reversed by Nicalin.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, co-localization, subcellular fractionation, co-immunoprecipitation in HEK293 cells\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — IP/MS identification of interacting protein validated by co-IP and co-localization, functional consequence described, single lab\",\n      \"pmids\": [\"32914261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of EphA7 kinase domain mutants Gly656Arg, Gly656Glu, and Asp751His reveal structural changes in the hinge region and nucleotide-binding groove; Gly656Arg and Asp751His show secondary structural changes affecting open/closed kinase conformation transitions; Asp751His shows a distorted nucleotide-binding groove; differences in hydrogen bonding and hydrophobic interactions in the DFG motif suggest these mutations influence catalytic activity.\",\n      \"method\": \"X-ray crystallography of kinase domain mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structures provide direct structural evidence, but functional catalytic activity not directly measured in this study; structural inferences about DFG motif\",\n      \"pmids\": [\"34186436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAT3 transcriptionally activates EphA7 expression in ESCC cells; ChIP assay identified the -2000 to -1500 region as the key EphA7 promoter bound by STAT3; STAT3 inhibition (Stattic) reduces EphA7 protein expression while IL-6-mediated STAT3 activation upregulates it; EphA7 is required for STAT3 activation-driven cell proliferation of ESCC.\",\n      \"method\": \"ChIP assay, truncated promoter/luciferase assay, STAT3 inhibitor treatment, IL-6 stimulation, siRNA knockdown, RNA-seq\",\n      \"journal\": \"Acta oncologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies direct promoter binding with luciferase reporter confirmation, pharmacological and genetic modulation with functional readout, single lab\",\n      \"pmids\": [\"37738252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 (the N6-adenosine-methyltransferase catalytic subunit) stabilizes EPHA7 expression through an m6A-dependent mechanism; chidamide downregulates METTL3, thereby reducing EPHA7; overexpression of EPHA7 counteracts METTL3 silencing effects, placing EPHA7 downstream of METTL3 in the same axis.\",\n      \"method\": \"METTL3 overexpression/silencing, EPHA7 overexpression rescue, in vivo xenograft, western blotting\",\n      \"journal\": \"Journal of chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis (overexpression rescue) with in vivo validation identifies post-transcriptional regulation by m6A, single lab, mechanism of m6A effect on EPHA7 not directly biochemically confirmed in abstract\",\n      \"pmids\": [\"40586624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"tRFAla-AGC-3-M8 (a tRNA-derived small RNA) directly targets EphA7 mRNA (validated by dual-luciferase reporter assay); in Alzheimer's disease (APP/PS1 mice), EphA7 is upregulated in microglia and neurons, with increased ERK1/2 and p70S6K phosphorylation; EphA7 siRNA knockdown suppresses ERK1/2-p70S6K signaling, reduces tau hyperphosphorylation in neurons, and reduces M1-type polarization of microglia.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, western blotting, immunofluorescence, APP/PS1 transgenic mice\",\n      \"journal\": \"Alzheimer's research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay, in vitro and in vivo functional dissection of EphA7-ERK1/2-p70S6K pathway, single lab with multiple methods\",\n      \"pmids\": [\"40375351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cervical cancer, SP1 and MAZ bind the EphA7 promoter (identified by CRISPR-mediated pull-down); EphA7 expression is regulated by SP1/DNMT1 (but not MAZ); 17-β-estradiol (E2) upregulates EphA7 expression through demethylation via the SP1/DNMT1 axis; CRISPR-based demethylation (dCas9-Tet1) reactivates EphA7 and suppresses tumor proliferation/invasion via PI3K/AKT signaling.\",\n      \"method\": \"CRISPR-mediated promoter pull-down, SP1/DNMT1 perturbation, dCas9-Tet1 demethylation, luciferase assay, western blotting for PI3K/AKT\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel CRISPR pull-down identifies upstream regulators, functional rescue by targeted demethylation with pathway readout, single lab\",\n      \"pmids\": [\"40258813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EphA7+ pericytes (CapSCs) isolated from mouse microvasculature are multipotent cells distinct from EphA7- control pericytes; EphA7 identifies a subpopulation with high multipotency, differentiating into mesenchymal, neuronal, endothelial, and pericyte lineages; transplantation of CapSCs into ischemic tissues improves blood flow recovery and vascular formation.\",\n      \"method\": \"FACS isolation, microarray identification of EphA7 as marker, in vitro multipotency assays, in vivo transplantation in hindlimb ischemia model\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FACS-based isolation and functional validation of EphA7 as pericyte subpopulation marker, in vivo transplantation with functional readout, single lab\",\n      \"pmids\": [\"31471947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In human rhabdomyosarcoma (hRMS) cells, EphA7 binds and signals through ephrin-A2 (rather than ephrin-A5 as in normal muscle), and both EphA7-Fc and ephrin-A5-Fc are potent inhibitors of hRMS proliferation in vitro.\",\n      \"method\": \"Binding assays, Fc-chimera proliferation assays, expression profiling of Eph/ephrin in hRMS vs. normal muscle\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — binding and functional proliferation assays identify divergent receptor-ligand specificity in hRMS, single lab\",\n      \"pmids\": [\"40426233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EphA7 is a receptor tyrosine kinase that produces full-length (TK+) and truncated/soluble kinase-domain-lacking isoforms with opposing functions: the TK+ isoform mediates repulsive ephrin-A signaling to guide corticothalamic axon topography, restrict dendritic growth, and regulate cortical domain formation, while the TK- isoform acts as a dominant-negative modulator and can enhance dendritic spine density; ligand-dependent phosphorylation of EphA7 is essential for its tumor-suppressive functions (via PI3K/Akt dephosphorylation, Bax/caspase-3/Bcl-2 modulation) and its pro-differentiation role in skeletal muscle; EphA7 also forms multi-protein complexes with TNFR1 upon ephrinA5 stimulation to induce caspase-dependent apoptosis, regulates inhibitory synaptic connectivity via mTOR-gephyrin-collybistin signaling, promotes HSPC maintenance via Rac1 activation, and is transcriptionally controlled by multiple regulators including HOXA13/HOXD13, STAT3, BMI-1 (via H3K27me3), and methylation of its promoter CpG island.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPHA7 is an ephrin-A receptor tyrosine kinase that guides topographic axon and tissue patterning during development and acts as a context-dependent regulator of cell survival and differentiation [#0, #2, #13]. The gene produces a full-length kinase-active isoform (TK+) and a truncated isoform lacking the kinase domain (TK-) that are distributed in distinct neuronal compartments and exert opposing actions: the kinase-active isoform mediates repulsive ephrin-A signaling to control corticothalamic projection topography, restrict dendritic growth, and regulate cortical domain formation, whereas the truncated isoform dimerizes with and dampens phosphorylation of the full-length receptor, behaving as a dominant-negative modulator that can instead increase dendritic spine density [#2, #3, #14]. EphA7 signaling restricts dendritic extent through Src and Tsc1 and stabilizes GABAergic inhibitory synaptic terminals through an mTOR–gephyrin–collybistin axis essential for hippocampal LTP and learning [#6, #8]. In peripheral tissues EphA7 directs nephric duct insertion via ephrin-B2, spiral ganglion neuron innervation of cochlear hair cells through ERK1/2, and skeletal muscle differentiation by promoting myoblast apoptosis and terminal commitment through juxtacrine contact [#7, #16, #13]. Ligand-dependent receptor phosphorylation underlies a tumor-suppressive function in which EphA7 induces apoptosis via Bax/caspase-3/Bcl-2 modulation and dephosphorylation of Akt, and a kinase-dead or cytoplasmic-domain-deleted receptor loses this activity [#10]. Beyond its kinase signaling, EphA7 forms a death-inducing complex with TNFR1 upon ephrinA5 stimulation to trigger caspase-dependent apoptosis, and serves as a cell-surface receptor for KSHV gH/gL-mediated viral entry and transmission [#5, #11]. EphA7 transcription is tightly controlled by HOXA13/HOXD13, STAT3, SP1/DNMT1, and Satb2, and is silenced by BMI-1-directed H3K27 trimethylation and promoter CpG methylation [#1, #17, #25, #19, #18, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that EphA7 is expressed as two functionally distinct isoforms with separate subcellular distributions, framing the gene as more than a single repulsive receptor.\",\n      \"evidence\": \"Isoform-specific antibody immunohistochemistry in adult mouse brain\",\n      \"pmids\": [\"10640696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue distinguishing isoform roles in this study\", \"Dominant-negative model inferred from localization, not tested biochemically\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that EphA7 on cortical axons sets corticothalamic projection topography, defining its developmental axon-guidance role in vivo.\",\n      \"evidence\": \"In utero electroporation mis-expression and axon tracing in mouse cortex\",\n      \"pmids\": [\"16301174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand and downstream effectors of the topographic signal not identified here\", \"Gain-of-function only\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified EphA7 as a direct transcriptional target of paralog-group-13 Hox proteins, linking limb patterning programs to its expression.\",\n      \"evidence\": \"In vivo ChIP, promoter reporter, and binding-site mutagenesis in mouse limb\",\n      \"pmids\": [\"16314414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Hox-driven EphA7 in limb morphogenesis not dissected\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that the TK+/TK- isoform ratio shifts across cortical development and that EphA7 controls ephrin-A5 distribution and cortical area size, establishing it as a regulator of cortical domain formation.\",\n      \"evidence\": \"EphA7-/- mouse analysis with isoform expression profiling and cortical area measurements\",\n      \"pmids\": [\"16615124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which isoform ratio is regulated unknown\", \"Direct measurement of repulsive signaling strength absent\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended Hox control to genital tubercle vasculature and revealed leukemogenic fusion proteins can hijack the EphA7 promoter, showing context-specific transcriptional regulation tied to ERK signaling.\",\n      \"evidence\": \"ChIP, transcriptional activation assays, Hoxa13 mutant mice, and ALL1-fusion knockdown with ERK/apoptosis readouts\",\n      \"pmids\": [\"17304517\", \"17726105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EphA7 kinase activity drives ERK in leukemic cells not resolved\", \"Direct vs indirect ERK coupling unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a kinase-independent death pathway in which ephrinA5-bound EphA7 recruits TNFR1 to drive caspase-dependent apoptosis.\",\n      \"evidence\": \"EphrinA5-Fc pull-down, co-IP, and TNFR1 domain-deletion mutants with apoptosis assays\",\n      \"pmids\": [\"23657875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological setting of the EphA7-TNFR1 complex not defined\", \"Stoichiometry of the multiprotein complex unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the downstream effectors (Src, Tsc1) by which EphA7 restricts dendrite growth and later promotes spine maturation, and showed EphA7/EphA4 from pericloacal mesenchyme signal via ephrin-B2 for nephric duct insertion.\",\n      \"evidence\": \"EphA7 KO with patterned substrates, electrophysiology, and compound/conditional knockout genetics\",\n      \"pmids\": [\"24707048\", \"25139858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single receptor switches from growth-restricting to spine-maturing not mechanistically resolved\", \"Direct biochemical link to ephrin-B2 reverse signaling inferred genetically\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed EphA7 upstream of ERK1/2 in spiral ganglion neuron innervation, generalizing its role in directed neuronal connectivity to the auditory system.\",\n      \"evidence\": \"EphA7 KO mice, SGN culture knockdown, ERK inhibitors, and Prkg1 knockout with electrophysiology\",\n      \"pmids\": [\"26178595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand identity for SGN signaling not specified\", \"Coupling of EphA7 to ERK1/2 mechanistically indirect\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected EphA7 to inhibitory synapse stability through an mTOR-gephyrin-collybistin axis, to HSPC adhesion/migration via Rac1, and revealed paralog-specific functions versus EphA4.\",\n      \"evidence\": \"In vivo knockdown with LTP/behavior, gephyrin co-IPs, ephrinA5-Fc HSPC assays with Rac1 inhibition, and comparative ligand-binding KO analysis\",\n      \"pmids\": [\"27405707\", \"27988259\", \"26587807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EphA7 activation engages mTOR not biochemically traced\", \"HSPC findings are Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified BMI-1 epigenetic silencing and an EPHA10 heterocomplex, broadening regulatory inputs and receptor-receptor interactions.\",\n      \"evidence\": \"BMI-1 overexpression with chromatin-modification analysis and EPHA7-EPHA10 co-IP/co-localization\",\n      \"pmids\": [\"27533460\", \"27566654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BMI-1 study lacks detailed method reporting\", \"EPHA10 interaction is single-lab co-IP without functional readout\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that ligand-dependent receptor phosphorylation is required for EphA7 tumor suppression via PI3K/Akt dephosphorylation and Bax/caspase-3/Bcl-2 modulation, and identified CLDN6 as a substrate in renal tubule morphogenesis.\",\n      \"evidence\": \"Phospho-site mutagenesis with xenograft/apoptosis assays in prostate cancer; Xenopus morpholino with CLDN6 binding and phosphorylation assays\",\n      \"pmids\": [\"29022918\", \"29223398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates linking phosphorylation to Akt dephosphorylation unknown\", \"CLDN6 work is Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed EphA7 is a functional receptor for KSHV gH/gL viral entry, defined Zfp422 enhancer control of EphA7-driven myoblast apoptosis, and identified EphA7 as a multipotent pericyte marker.\",\n      \"evidence\": \"Recombinant gH/gL precipitation with CRISPR KO infection assays; ChIP-Seq with Zfp422 KO and C2C12 differentiation; FACS isolation and ischemia transplantation\",\n      \"pmids\": [\"31118261\", \"31685980\", \"31471947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether viral receptor function requires kinase activity untested\", \"Pericyte marker role is Medium-confidence correlative isolation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated EphA7 drives skeletal muscle terminal differentiation by juxtacrine signaling and confirmed full-length and truncated isoforms physically interact to oppose each other in cortical dendrite development.\",\n      \"evidence\": \"EphA7 KO mice with ECD rescue and muscle analysis; isoform overexpression, co-IP, and in vivo rapamycin epistasis; Nicalin IP/MS and fractionation\",\n      \"pmids\": [\"32314958\", \"33275600\", \"32914261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mTOR-dependence switch across development not biochemically mapped\", \"Nicalin/sEphA7 ER trafficking role is Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural insight into how kinase-domain mutations alter hinge, DFG motif, and nucleotide-binding conformations relevant to catalytic regulation.\",\n      \"evidence\": \"X-ray crystallography of EphA7 kinase-domain point mutants\",\n      \"pmids\": [\"34186436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic activity of mutants not directly measured\", \"Functional consequence in cells not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined STAT3 as a direct activator of EphA7 required for STAT3-driven proliferation in esophageal squamous cell carcinoma, contrasting with its tumor-suppressive role elsewhere.\",\n      \"evidence\": \"ChIP, truncated-promoter luciferase, STAT3 inhibition, IL-6 stimulation, and siRNA with RNA-seq\",\n      \"pmids\": [\"37738252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why EphA7 is pro-proliferative in ESCC versus suppressive in prostate not reconciled\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the regulatory and effector network with m6A stabilization by METTL3, a tRNA-derived fragment targeting EphA7 mRNA in Alzheimer's models, SP1/DNMT1 demethylation control, and divergent ephrin-A2 usage in rhabdomyosarcoma.\",\n      \"evidence\": \"METTL3 epistasis with xenograft; dual-luciferase tRF targeting with ERK1/2-p70S6K dissection in APP/PS1 mice; CRISPR promoter pull-down with dCas9-Tet1 demethylation; Fc-chimera binding/proliferation assays in hRMS\",\n      \"pmids\": [\"40586624\", \"40375351\", \"40258813\", \"40426233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical site of m6A on EPHA7 not confirmed\", \"Ligand-specificity switch mechanism in tumors unresolved\", \"All single-lab Medium-confidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor reconciles opposing tumor-suppressive (Akt dephosphorylation, apoptosis) and tumor-promoting (STAT3-driven proliferation) outcomes, and how isoform ratio, ligand identity, and phosphorylation state are coordinated to select among repulsion, apoptosis, differentiation, and viral entry, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phosphorylation-dependent and kinase-independent functions\", \"Context-determinants of pro- vs anti-tumor signaling unknown\", \"In vivo substrate repertoire of the kinase undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 21, 22, 24]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 15, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 7, 13, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 10, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 17, 18, 19, 25, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 10, 11, 25, 28]}\n    ],\n    \"complexes\": [\n      \"EphA7-TNFR1 ephrinA5-induced death complex\",\n      \"EphA7-EPHA10 receptor heterocomplex\"\n    ],\n    \"partners\": [\n      \"EFNA5\",\n      \"TNFR1\",\n      \"EPHA10\",\n      \"CLDN6\",\n      \"NCLN\",\n      \"EFNB2\",\n      \"EFNA2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}