{"gene":"MEIS3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"Zebrafish Pbx4 forms binary complexes with Meis3 or Hoxb1b, and a trimeric complex containing Pbx4, Meis3, and Hoxb1b, as demonstrated by in vitro binding experiments. Meis3/Hoxb1b cannot form a complex without Pbx4.","method":"In vitro protein binding assays","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding established complex formation, single lab, single method","pmids":["10679934"],"is_preprint":false},{"year":2001,"finding":"In zebrafish, Meis3 synergizes with Pbx4 and Hoxb1b to promote hindbrain fates; this synergy requires intact Pbx-interaction domains on both Hoxb1b and Meis3, and Meis3 binding to Pbx4 is required for its nuclear access.","method":"Gain-of-function overexpression in zebrafish embryos, domain mutagenesis, subcellular localization assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional epistasis with domain mutagenesis and nuclear localization assay, multiple orthogonal approaches in one study","pmids":["11262231"],"is_preprint":false},{"year":2003,"finding":"In Xenopus, XMeis3 protein establishes a hindbrain-inducing center by activating FGF/MAP-kinase signaling, which in turn modulates the Wnt-PCP pathway, inducing convergent extension cell movements and hindbrain marker expression in adjacent neuralized tissue.","method":"Explant recombination assay, knockdown (morpholino), pathway inhibition experiments","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis established via explant assay, pathway inhibitors, and knockdown; multiple orthogonal methods in one study","pmids":["14660437"],"is_preprint":false},{"year":2004,"finding":"In Xenopus, XMeis3 protein and retinoic acid (RA) signaling interact to regulate hindbrain patterning: XMeis3 is required for RA-induced caudalizing activity, and RA modifies XMeis3 transcriptional activity in a target-gene-dependent manner. HoxD1 is identified as a direct target gene of both RA and XMeis3.","method":"Morpholino knockdown, explant assays, RA signaling inhibition, target gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown combined with RA pathway inhibition and target gene analysis, single lab","pmids":["15196951"],"is_preprint":false},{"year":2009,"finding":"In Xenopus, XMeis3 protein acts downstream of Pax3, Zic1, and Zic5 in the genetic cascade controlling neural cell specification; XMeis3 knockdown eliminates hindbrain, neural crest, and primary neuron fates without altering Zic/Pax3 expression; ectopic XMeis3 rescues Zic knockdown phenotype. FGF3 and FGF8 are direct target genes of XMeis3, and HoxD1 is also a direct XMeis3 target.","method":"Morpholino knockdown, ectopic expression rescue, target gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by knockdown and rescue, direct target identification, single lab","pmids":["19944089"],"is_preprint":false},{"year":2010,"finding":"Wnt3a from the paraxial dorsolateral mesoderm directly activates Meis3 expression in overlying neuroectoderm via Wnt/beta-catenin signaling; ectopic Meis3 rescues loss of posterior neural fates caused by Wnt3a loss; Meis3 is required downstream of Wnt3a for posterior nervous system induction. Meis3 was shown to be a direct transcriptional target of Wnt/beta-catenin by ChIP and promoter analysis.","method":"Loss-of-function (Wnt3a knockout), ectopic expression rescue, ChIP, promoter analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP and promoter analysis establish direct target, loss-of-function with rescue confirms pathway position, multiple orthogonal methods","pmids":["20356957"],"is_preprint":false},{"year":2010,"finding":"Meis3 regulates β-cell survival by directly activating expression of PDK1 (3-phosphoinositide-dependent protein kinase 1), a kinase in the PI3K-Akt pathway; this was also shown in ovarian carcinoma cells.","method":"Gene knockdown/overexpression, direct target gene analysis, cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target identification with functional survival readout in two cell types, single lab","pmids":["21059917"],"is_preprint":false},{"year":2012,"finding":"In Xenopus, Meis3 forms a transcriptional complex with Tsh1 protein; upon strong Wnt3a/Meis3 feedback loop activity, Tsh1 is induced and the Meis3-Tsh1 complex represses the Meis3 promoter, enabling cell cycle exit and neuronal differentiation. Functional and biochemical analyses established this circuit.","method":"Biochemical co-complex analysis, functional epistasis, promoter repression assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction and functional epistasis with promoter analysis, single lab","pmids":["22399680"],"is_preprint":false},{"year":2015,"finding":"In zebrafish, Meis3 loss-of-function reduces neural crest cell migration efficiency, cell number, and mitotic activity near the gut, leading to colonic aganglionosis; Meis3 depletion misregulates Shh pathway components in the gut, placing Meis3 upstream of Shh signaling in enteric nervous system development.","method":"Morpholino knockdown, cell migration and proliferation assays, marker gene expression analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular and molecular phenotypes, pathway placement via downstream marker analysis, single lab","pmids":["26354419"],"is_preprint":false},{"year":2021,"finding":"In HCC cells, HOXA1 increases H3K4me1 and H3K27ac enrichment at the MEIS3 enhancer region to enhance MEIS3 expression; this was shown by ChIP assay demonstrating HOXA1 interaction with the MEIS3 enhancer.","method":"ChIP assay, dual-luciferase reporter assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP demonstrates direct epigenetic regulation of MEIS3 by HOXA1, single lab, single method for this specific finding","pmids":["33520978"],"is_preprint":false},{"year":2022,"finding":"In Xenopus, Meis3 (along with Hoxb4 and Pbx1) directly transactivates a pax8 enhancer (Pax8-CNS1) to control pax8 expression in the kidney field; mutagenesis of PBX-Hox binding motifs in Pax8-CNS1 identified two sites necessary for transactivation. Meis3 depletion severely inhibits pax8 expression but only marginally affects lhx1 expression, placing Meis3 upstream of pax8 in renal specification.","method":"Morpholino knockdown, reporter assay with enhancer deletions and mutagenesis, animal cap expression assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — enhancer mutagenesis combined with reporter assay and morpholino knockdown establishes direct transcriptional mechanism, multiple orthogonal methods","pmids":["36279927"],"is_preprint":false},{"year":2026,"finding":"MEIS3 protein binds allele-specifically to the rs113671272 regulatory variant in the AGPS 5'UTR (active enhancer marked by H3K27ac/H3K4me1/H3K4me3); MEIS3 knockdown suppresses AGPS expression; MEIS3 promotes ESCC cell proliferation and migration as part of a MEIS3/AGPS/NF-κB regulatory axis.","method":"CUT&Tag-qPCR, EMSA, RNA interference (knockdown), in vitro and in vivo (xenograft) models, Western blotting","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific binding confirmed by EMSA and CUT&Tag, direct target regulation by knockdown, multiple orthogonal methods, single lab","pmids":["41950565"],"is_preprint":false}],"current_model":"MEIS3 is a TALE homeodomain transcription factor that acts as a context-dependent transcriptional activator or repressor: it forms binary and trimeric complexes with PBX and HOX proteins (requiring intact PBX-interaction domains for both activity and nuclear localization), is directly activated by Wnt/beta-catenin signaling from adjacent mesoderm, activates FGF/MAP-kinase and Wnt-PCP signaling to induce hindbrain and posterior neural fates, regulates cell survival via direct transcriptional activation of PDK1, forms a repressive complex with Tsh1 to restrain its own promoter and coordinate neuronal differentiation, controls neural crest migration and enteric nervous system development via the Shh pathway, and directly transactivates tissue-specific enhancers (e.g., pax8 in the kidney field and AGPS in cancer) through PBX-HOX binding motifs."},"narrative":{"mechanistic_narrative":"MEIS3 is a TALE-class homeodomain transcription factor that operates as a hub linking posteriorizing signals to neural and tissue patterning programs [PMID:20356957, PMID:14660437]. It partners with PBX and HOX proteins, forming binary complexes with Pbx4 or Hoxb1b and a trimeric Pbx4–Meis3–Hoxb1b complex; this synergy to drive hindbrain fates requires intact PBX-interaction domains, and Meis3 binding to Pbx4 is itself required for Meis3 nuclear access [PMID:10679934, PMID:11262231]. As a transcription factor it directly transactivates target enhancers through PBX–HOX binding motifs, demonstrated for a pax8 kidney-field enhancer (with Hoxb4 and Pbx1) and for posterior neural targets including HoxD1 and FGF3/FGF8 [PMID:36279927, PMID:19944089]. In neural development, Meis3 is a direct transcriptional target of Wnt3a/beta-catenin signaling from adjacent paraxial mesoderm and is required downstream of Wnt3a to induce posterior nervous system fates [PMID:20356957]; it establishes a hindbrain-inducing center by activating FGF/MAP-kinase signaling, which modulates the Wnt-PCP pathway to drive convergent extension and hindbrain marker expression [PMID:14660437]. A Meis3–Tsh1 repressive complex acts on the Meis3 promoter to terminate this Wnt/Meis3 feedback loop, permitting cell cycle exit and neuronal differentiation [PMID:22399680]. Beyond neural induction, Meis3 controls neural crest cell migration, proliferation, and enteric nervous system development upstream of Shh signaling [PMID:26354419], regulates cell survival through direct activation of PDK1 [PMID:21059917], and contributes to cancer by binding allele-specific regulatory variants to drive target expression such as AGPS in esophageal carcinoma [PMID:41950565].","teleology":[{"year":2000,"claim":"Established the biochemical basis for MEIS3 function by showing it assembles into HOX/PBX transcription factor complexes rather than acting alone.","evidence":"In vitro protein binding assays with zebrafish Pbx4, Meis3, and Hoxb1b","pmids":["10679934"],"confidence":"Medium","gaps":["In vitro binding only; no demonstration of complex on DNA or in vivo","DNA-binding specificity of the trimer not defined"]},{"year":2001,"claim":"Connected MEIS3 complex formation to function and localization, showing PBX interaction is required both for hindbrain-promoting synergy and for MEIS3 nuclear access.","evidence":"Gain-of-function overexpression, domain mutagenesis, and subcellular localization assays in zebrafish embryos","pmids":["11262231"],"confidence":"High","gaps":["Direct target genes of the synergistic complex not identified here","Mechanism coupling PBX binding to nuclear import unresolved"]},{"year":2003,"claim":"Defined the downstream signaling output of MEIS3, showing it creates a hindbrain-inducing center via FGF/MAP-kinase activation feeding into Wnt-PCP-driven morphogenesis.","evidence":"Explant recombination assays, morpholino knockdown, and pathway inhibition in Xenopus","pmids":["14660437"],"confidence":"High","gaps":["Direct FGF target genes not yet identified at this stage","Molecular link between MEIS3 and PCP components indirect"]},{"year":2004,"claim":"Placed MEIS3 in the retinoic acid caudalizing network and identified HoxD1 as a shared direct target, framing MEIS3 as a context-dependent integrator of patterning signals.","evidence":"Morpholino knockdown, explant assays, RA inhibition, and target gene analysis in Xenopus","pmids":["15196951"],"confidence":"Medium","gaps":["Mechanism by which RA modifies MEIS3 activity not defined","Direct binding to HoxD1 regulatory elements not shown"]},{"year":2009,"claim":"Positioned MEIS3 within the neural specification cascade downstream of Pax3/Zic and identified FGF3, FGF8, and HoxD1 as direct targets, explaining its requirement for hindbrain, neural crest, and primary neuron fates.","evidence":"Morpholino knockdown, ectopic expression rescue, and target gene analysis in Xenopus","pmids":["19944089"],"confidence":"Medium","gaps":["Direct enhancer binding for FGF3/FGF8 not mapped","Cooperating PBX/HOX partners at these targets not defined"]},{"year":2010,"claim":"Identified the upstream inductive signal, showing Wnt3a/beta-catenin from paraxial mesoderm directly activates MEIS3 to induce posterior neural fate.","evidence":"Wnt3a loss-of-function, ectopic expression rescue, ChIP, and promoter analysis","pmids":["20356957"],"confidence":"High","gaps":["beta-catenin/TCF binding sites in the Meis3 promoter not finely mapped","Tissue-specificity of Wnt-driven activation not fully resolved"]},{"year":2010,"claim":"Extended MEIS3 function beyond patterning to cell survival by identifying PDK1 as a direct target linking it to the PI3K-Akt pathway in beta-cells and ovarian carcinoma.","evidence":"Knockdown/overexpression, direct target analysis, and survival assays in two cell types","pmids":["21059917"],"confidence":"Medium","gaps":["Cofactors at the PDK1 promoter not identified","Generalizability across cell types beyond the two tested unknown"]},{"year":2012,"claim":"Revealed an autoregulatory off-switch in which a MEIS3-Tsh1 repressive complex shuts down the Meis3 promoter to permit cell cycle exit and neuronal differentiation.","evidence":"Biochemical co-complex analysis, functional epistasis, and promoter repression assays in Xenopus","pmids":["22399680"],"confidence":"Medium","gaps":["Structural basis of the Meis3-Tsh1 interaction not defined","Whether the same complex acts on other targets unknown"]},{"year":2015,"claim":"Demonstrated a role in enteric nervous system development, placing MEIS3 upstream of Shh signaling in neural crest migration and proliferation toward the gut.","evidence":"Morpholino knockdown, migration and proliferation assays, and marker analysis in zebrafish","pmids":["26354419"],"confidence":"Medium","gaps":["Direct Shh-pathway target genes of MEIS3 not identified","Whether the effect is cell-autonomous in crest cells unresolved"]},{"year":2022,"claim":"Provided direct evidence for the enhancer-level mechanism, showing MEIS3 with Hoxb4 and Pbx1 transactivates a pax8 enhancer through defined PBX-HOX motifs in renal specification.","evidence":"Morpholino knockdown, enhancer deletion/mutagenesis reporter assays, and animal cap assays in Xenopus","pmids":["36279927"],"confidence":"High","gaps":["In vivo occupancy of the endogenous Pax8-CNS1 enhancer not shown by ChIP","Selectivity over lhx1 mechanistically unexplained"]},{"year":2021,"claim":"Identified an upstream epigenetic regulator of MEIS3, showing HOXA1 deposits activating histone marks at the MEIS3 enhancer in hepatocellular carcinoma.","evidence":"ChIP assay and dual-luciferase reporter assay in HCC cells","pmids":["33520978"],"confidence":"Medium","gaps":["Single method for the HOXA1-MEIS3 link","Downstream MEIS3 effectors in HCC not defined"]},{"year":2026,"claim":"Extended MEIS3's enhancer-binding role to cancer, showing allele-specific binding to a regulatory variant that drives AGPS expression through a MEIS3/AGPS/NF-kB axis in esophageal carcinoma.","evidence":"CUT&Tag-qPCR, EMSA, RNAi, xenograft models, and Western blotting in ESCC cells","pmids":["41950565"],"confidence":"Medium","gaps":["Whether PBX/HOX partners participate at the AGPS variant not tested","Mechanism linking AGPS to NF-kB activation not fully resolved"]},{"year":null,"claim":"How MEIS3's binary versus trimeric PBX-HOX complex composition selects between activator and repressor outputs at distinct target enhancers remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MEIS3 on DNA with partners","Genome-wide direct binding map not established","Rules governing context-dependent activation versus repression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,10,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,4,8,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,8]}],"complexes":["Pbx4-Meis3-Hoxb1b trimeric complex","Meis3-Tsh1 repressive complex"],"partners":["PBX4","PBX1","HOXB1B","HOXB4","TSH1","HOXA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99687","full_name":"Homeobox protein Meis3","aliases":["Meis1-related protein 2"],"length_aa":375,"mass_kda":41.1,"function":"Transcriptional regulator which directly modulates PDPK1 expression, thus promoting survival of pancreatic beta-cells. Also regulates expression of NDFIP1, BNIP3, and CCNG1","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99687/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEIS3","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEIS3","total_profiled":1310},"omim":[{"mim_id":"619443","title":"MEIS HOMEOBOX 3; MEIS3","url":"https://www.omim.org/entry/619443"},{"mim_id":"602100","title":"PBX/KNOTTED 1 HOMEOBOX 1; PKNOX1","url":"https://www.omim.org/entry/602100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":115.2},{"tissue":"endometrium 1","ntpm":79.8}],"url":"https://www.proteinatlas.org/search/MEIS3"},"hgnc":{"alias_symbol":["MRG2","DKFZp547H236"],"prev_symbol":[]},"alphafold":{"accession":"Q99687","domains":[{"cath_id":"1.10.10.60","chopping":"268-329","consensus_level":"high","plddt":91.6802,"start":268,"end":329},{"cath_id":"1.20.58","chopping":"54-84_99-166","consensus_level":"high","plddt":87.2926,"start":54,"end":166}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99687","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99687-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99687-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEIS3","jax_strain_url":"https://www.jax.org/strain/search?query=MEIS3"},"sequence":{"accession":"Q99687","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99687.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99687/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99687"}},"corpus_meta":[{"pmid":"11262231","id":"PMC_11262231","title":"Meis3 synergizes with Pbx4 and Hoxb1b in promoting hindbrain fates in the zebrafish.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11262231","citation_count":85,"is_preprint":false},{"pmid":"20356957","id":"PMC_20356957","title":"Mesodermal Wnt signaling organizes the neural plate via Meis3.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20356957","citation_count":50,"is_preprint":false},{"pmid":"10679934","id":"PMC_10679934","title":"A novel pbx family member expressed during early zebrafish embryogenesis forms trimeric complexes with Meis3 and Hoxb1b.","date":"2000","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/10679934","citation_count":45,"is_preprint":false},{"pmid":"26354419","id":"PMC_26354419","title":"Meis3 is required for neural crest invasion of the gut during zebrafish enteric nervous system development.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26354419","citation_count":38,"is_preprint":false},{"pmid":"14660437","id":"PMC_14660437","title":"Xenopus Meis3 protein forms a hindbrain-inducing center by activating FGF/MAP kinase and PCP pathways.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/14660437","citation_count":31,"is_preprint":false},{"pmid":"19944089","id":"PMC_19944089","title":"Xenopus Meis3 protein lies at a nexus downstream to Zic1 and Pax3 proteins, regulating multiple cell-fates during early nervous system development.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19944089","citation_count":30,"is_preprint":false},{"pmid":"21059917","id":"PMC_21059917","title":"Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21059917","citation_count":24,"is_preprint":false},{"pmid":"33520978","id":"PMC_33520978","title":"Tumor-Suppressive Role of microRNA-202-3p in Hepatocellular Carcinoma Through the KDM3A/HOXA1/MEIS3 Pathway.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33520978","citation_count":23,"is_preprint":false},{"pmid":"22399680","id":"PMC_22399680","title":"A hindbrain-repressive Wnt3a/Meis3/Tsh1 circuit promotes neuronal differentiation and coordinates tissue maturation.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22399680","citation_count":21,"is_preprint":false},{"pmid":"15196951","id":"PMC_15196951","title":"The Meis3 protein and retinoid signaling interact to pattern the Xenopus hindbrain.","date":"2004","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15196951","citation_count":19,"is_preprint":false},{"pmid":"18223676","id":"PMC_18223676","title":"Acceleration of chronic myeloproliferation by enforced expression of Meis1 or Meis3 in Icsbp-deficient bone marrow cells.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18223676","citation_count":7,"is_preprint":false},{"pmid":"35180817","id":"PMC_35180817","title":"The impact of glutamine deprivation on the expression of MEIS3, SPAG4, LHX1, LHX2, and LHX6 genes in ERN1 knockdown U87 glioma cells.","date":"2022","source":"Endocrine regulations","url":"https://pubmed.ncbi.nlm.nih.gov/35180817","citation_count":4,"is_preprint":false},{"pmid":"33376716","id":"PMC_33376716","title":"Inhibition of MEIS3 Generates Cetuximab Resistance through c-Met and Akt.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33376716","citation_count":3,"is_preprint":false},{"pmid":"26763390","id":"PMC_26763390","title":"MEIS3 is repressed in A549 lung epithelial cells by deoxynivalenol and the repression contributes to the deleterious effect.","date":"2016","source":"The Journal of toxicological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26763390","citation_count":1,"is_preprint":false},{"pmid":"41200169","id":"PMC_41200169","title":"Integrative multi-omics identifies MEIS3 as a diagnostic biomarker and immune modulator in hypertrophic cardiomyopathy.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41200169","citation_count":0,"is_preprint":false},{"pmid":"36279927","id":"PMC_36279927","title":"Retinoic acid control of pax8 during renal specification of Xenopus pronephros involves hox and meis3.","date":"2022","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36279927","citation_count":0,"is_preprint":false},{"pmid":"41950565","id":"PMC_41950565","title":"The AGPS regulatory variant rs113671272 confers esophageal squamous cell carcinoma susceptibility through allele-specific MEIS3 binding and NF-κB activation in Chinese populations.","date":"2026","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41950565","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10315,"output_tokens":2948,"usd":0.037582,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10268,"output_tokens":3882,"usd":0.074195,"stage2_stop_reason":"end_turn"},"total_usd":0.111777,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Zebrafish Pbx4 forms binary complexes with Meis3 or Hoxb1b, and a trimeric complex containing Pbx4, Meis3, and Hoxb1b, as demonstrated by in vitro binding experiments. Meis3/Hoxb1b cannot form a complex without Pbx4.\",\n      \"method\": \"In vitro protein binding assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding established complex formation, single lab, single method\",\n      \"pmids\": [\"10679934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In zebrafish, Meis3 synergizes with Pbx4 and Hoxb1b to promote hindbrain fates; this synergy requires intact Pbx-interaction domains on both Hoxb1b and Meis3, and Meis3 binding to Pbx4 is required for its nuclear access.\",\n      \"method\": \"Gain-of-function overexpression in zebrafish embryos, domain mutagenesis, subcellular localization assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis with domain mutagenesis and nuclear localization assay, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"11262231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Xenopus, XMeis3 protein establishes a hindbrain-inducing center by activating FGF/MAP-kinase signaling, which in turn modulates the Wnt-PCP pathway, inducing convergent extension cell movements and hindbrain marker expression in adjacent neuralized tissue.\",\n      \"method\": \"Explant recombination assay, knockdown (morpholino), pathway inhibition experiments\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via explant assay, pathway inhibitors, and knockdown; multiple orthogonal methods in one study\",\n      \"pmids\": [\"14660437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Xenopus, XMeis3 protein and retinoic acid (RA) signaling interact to regulate hindbrain patterning: XMeis3 is required for RA-induced caudalizing activity, and RA modifies XMeis3 transcriptional activity in a target-gene-dependent manner. HoxD1 is identified as a direct target gene of both RA and XMeis3.\",\n      \"method\": \"Morpholino knockdown, explant assays, RA signaling inhibition, target gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown combined with RA pathway inhibition and target gene analysis, single lab\",\n      \"pmids\": [\"15196951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Xenopus, XMeis3 protein acts downstream of Pax3, Zic1, and Zic5 in the genetic cascade controlling neural cell specification; XMeis3 knockdown eliminates hindbrain, neural crest, and primary neuron fates without altering Zic/Pax3 expression; ectopic XMeis3 rescues Zic knockdown phenotype. FGF3 and FGF8 are direct target genes of XMeis3, and HoxD1 is also a direct XMeis3 target.\",\n      \"method\": \"Morpholino knockdown, ectopic expression rescue, target gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by knockdown and rescue, direct target identification, single lab\",\n      \"pmids\": [\"19944089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt3a from the paraxial dorsolateral mesoderm directly activates Meis3 expression in overlying neuroectoderm via Wnt/beta-catenin signaling; ectopic Meis3 rescues loss of posterior neural fates caused by Wnt3a loss; Meis3 is required downstream of Wnt3a for posterior nervous system induction. Meis3 was shown to be a direct transcriptional target of Wnt/beta-catenin by ChIP and promoter analysis.\",\n      \"method\": \"Loss-of-function (Wnt3a knockout), ectopic expression rescue, ChIP, promoter analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP and promoter analysis establish direct target, loss-of-function with rescue confirms pathway position, multiple orthogonal methods\",\n      \"pmids\": [\"20356957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Meis3 regulates β-cell survival by directly activating expression of PDK1 (3-phosphoinositide-dependent protein kinase 1), a kinase in the PI3K-Akt pathway; this was also shown in ovarian carcinoma cells.\",\n      \"method\": \"Gene knockdown/overexpression, direct target gene analysis, cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target identification with functional survival readout in two cell types, single lab\",\n      \"pmids\": [\"21059917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Xenopus, Meis3 forms a transcriptional complex with Tsh1 protein; upon strong Wnt3a/Meis3 feedback loop activity, Tsh1 is induced and the Meis3-Tsh1 complex represses the Meis3 promoter, enabling cell cycle exit and neuronal differentiation. Functional and biochemical analyses established this circuit.\",\n      \"method\": \"Biochemical co-complex analysis, functional epistasis, promoter repression assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction and functional epistasis with promoter analysis, single lab\",\n      \"pmids\": [\"22399680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In zebrafish, Meis3 loss-of-function reduces neural crest cell migration efficiency, cell number, and mitotic activity near the gut, leading to colonic aganglionosis; Meis3 depletion misregulates Shh pathway components in the gut, placing Meis3 upstream of Shh signaling in enteric nervous system development.\",\n      \"method\": \"Morpholino knockdown, cell migration and proliferation assays, marker gene expression analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular and molecular phenotypes, pathway placement via downstream marker analysis, single lab\",\n      \"pmids\": [\"26354419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In HCC cells, HOXA1 increases H3K4me1 and H3K27ac enrichment at the MEIS3 enhancer region to enhance MEIS3 expression; this was shown by ChIP assay demonstrating HOXA1 interaction with the MEIS3 enhancer.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP demonstrates direct epigenetic regulation of MEIS3 by HOXA1, single lab, single method for this specific finding\",\n      \"pmids\": [\"33520978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Xenopus, Meis3 (along with Hoxb4 and Pbx1) directly transactivates a pax8 enhancer (Pax8-CNS1) to control pax8 expression in the kidney field; mutagenesis of PBX-Hox binding motifs in Pax8-CNS1 identified two sites necessary for transactivation. Meis3 depletion severely inhibits pax8 expression but only marginally affects lhx1 expression, placing Meis3 upstream of pax8 in renal specification.\",\n      \"method\": \"Morpholino knockdown, reporter assay with enhancer deletions and mutagenesis, animal cap expression assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enhancer mutagenesis combined with reporter assay and morpholino knockdown establishes direct transcriptional mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"36279927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEIS3 protein binds allele-specifically to the rs113671272 regulatory variant in the AGPS 5'UTR (active enhancer marked by H3K27ac/H3K4me1/H3K4me3); MEIS3 knockdown suppresses AGPS expression; MEIS3 promotes ESCC cell proliferation and migration as part of a MEIS3/AGPS/NF-κB regulatory axis.\",\n      \"method\": \"CUT&Tag-qPCR, EMSA, RNA interference (knockdown), in vitro and in vivo (xenograft) models, Western blotting\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific binding confirmed by EMSA and CUT&Tag, direct target regulation by knockdown, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41950565\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEIS3 is a TALE homeodomain transcription factor that acts as a context-dependent transcriptional activator or repressor: it forms binary and trimeric complexes with PBX and HOX proteins (requiring intact PBX-interaction domains for both activity and nuclear localization), is directly activated by Wnt/beta-catenin signaling from adjacent mesoderm, activates FGF/MAP-kinase and Wnt-PCP signaling to induce hindbrain and posterior neural fates, regulates cell survival via direct transcriptional activation of PDK1, forms a repressive complex with Tsh1 to restrain its own promoter and coordinate neuronal differentiation, controls neural crest migration and enteric nervous system development via the Shh pathway, and directly transactivates tissue-specific enhancers (e.g., pax8 in the kidney field and AGPS in cancer) through PBX-HOX binding motifs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEIS3 is a TALE-class homeodomain transcription factor that operates as a hub linking posteriorizing signals to neural and tissue patterning programs [#5, #2]. It partners with PBX and HOX proteins, forming binary complexes with Pbx4 or Hoxb1b and a trimeric Pbx4–Meis3–Hoxb1b complex; this synergy to drive hindbrain fates requires intact PBX-interaction domains, and Meis3 binding to Pbx4 is itself required for Meis3 nuclear access [#0, #1]. As a transcription factor it directly transactivates target enhancers through PBX–HOX binding motifs, demonstrated for a pax8 kidney-field enhancer (with Hoxb4 and Pbx1) and for posterior neural targets including HoxD1 and FGF3/FGF8 [#10, #4]. In neural development, Meis3 is a direct transcriptional target of Wnt3a/beta-catenin signaling from adjacent paraxial mesoderm and is required downstream of Wnt3a to induce posterior nervous system fates [#5]; it establishes a hindbrain-inducing center by activating FGF/MAP-kinase signaling, which modulates the Wnt-PCP pathway to drive convergent extension and hindbrain marker expression [#2]. A Meis3–Tsh1 repressive complex acts on the Meis3 promoter to terminate this Wnt/Meis3 feedback loop, permitting cell cycle exit and neuronal differentiation [#7]. Beyond neural induction, Meis3 controls neural crest cell migration, proliferation, and enteric nervous system development upstream of Shh signaling [#8], regulates cell survival through direct activation of PDK1 [#6], and contributes to cancer by binding allele-specific regulatory variants to drive target expression such as AGPS in esophageal carcinoma [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the biochemical basis for MEIS3 function by showing it assembles into HOX/PBX transcription factor complexes rather than acting alone.\",\n      \"evidence\": \"In vitro protein binding assays with zebrafish Pbx4, Meis3, and Hoxb1b\",\n      \"pmids\": [\"10679934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro binding only; no demonstration of complex on DNA or in vivo\", \"DNA-binding specificity of the trimer not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected MEIS3 complex formation to function and localization, showing PBX interaction is required both for hindbrain-promoting synergy and for MEIS3 nuclear access.\",\n      \"evidence\": \"Gain-of-function overexpression, domain mutagenesis, and subcellular localization assays in zebrafish embryos\",\n      \"pmids\": [\"11262231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes of the synergistic complex not identified here\", \"Mechanism coupling PBX binding to nuclear import unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the downstream signaling output of MEIS3, showing it creates a hindbrain-inducing center via FGF/MAP-kinase activation feeding into Wnt-PCP-driven morphogenesis.\",\n      \"evidence\": \"Explant recombination assays, morpholino knockdown, and pathway inhibition in Xenopus\",\n      \"pmids\": [\"14660437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FGF target genes not yet identified at this stage\", \"Molecular link between MEIS3 and PCP components indirect\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed MEIS3 in the retinoic acid caudalizing network and identified HoxD1 as a shared direct target, framing MEIS3 as a context-dependent integrator of patterning signals.\",\n      \"evidence\": \"Morpholino knockdown, explant assays, RA inhibition, and target gene analysis in Xenopus\",\n      \"pmids\": [\"15196951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RA modifies MEIS3 activity not defined\", \"Direct binding to HoxD1 regulatory elements not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Positioned MEIS3 within the neural specification cascade downstream of Pax3/Zic and identified FGF3, FGF8, and HoxD1 as direct targets, explaining its requirement for hindbrain, neural crest, and primary neuron fates.\",\n      \"evidence\": \"Morpholino knockdown, ectopic expression rescue, and target gene analysis in Xenopus\",\n      \"pmids\": [\"19944089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enhancer binding for FGF3/FGF8 not mapped\", \"Cooperating PBX/HOX partners at these targets not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the upstream inductive signal, showing Wnt3a/beta-catenin from paraxial mesoderm directly activates MEIS3 to induce posterior neural fate.\",\n      \"evidence\": \"Wnt3a loss-of-function, ectopic expression rescue, ChIP, and promoter analysis\",\n      \"pmids\": [\"20356957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"beta-catenin/TCF binding sites in the Meis3 promoter not finely mapped\", \"Tissue-specificity of Wnt-driven activation not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended MEIS3 function beyond patterning to cell survival by identifying PDK1 as a direct target linking it to the PI3K-Akt pathway in beta-cells and ovarian carcinoma.\",\n      \"evidence\": \"Knockdown/overexpression, direct target analysis, and survival assays in two cell types\",\n      \"pmids\": [\"21059917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors at the PDK1 promoter not identified\", \"Generalizability across cell types beyond the two tested unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed an autoregulatory off-switch in which a MEIS3-Tsh1 repressive complex shuts down the Meis3 promoter to permit cell cycle exit and neuronal differentiation.\",\n      \"evidence\": \"Biochemical co-complex analysis, functional epistasis, and promoter repression assays in Xenopus\",\n      \"pmids\": [\"22399680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the Meis3-Tsh1 interaction not defined\", \"Whether the same complex acts on other targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a role in enteric nervous system development, placing MEIS3 upstream of Shh signaling in neural crest migration and proliferation toward the gut.\",\n      \"evidence\": \"Morpholino knockdown, migration and proliferation assays, and marker analysis in zebrafish\",\n      \"pmids\": [\"26354419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Shh-pathway target genes of MEIS3 not identified\", \"Whether the effect is cell-autonomous in crest cells unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct evidence for the enhancer-level mechanism, showing MEIS3 with Hoxb4 and Pbx1 transactivates a pax8 enhancer through defined PBX-HOX motifs in renal specification.\",\n      \"evidence\": \"Morpholino knockdown, enhancer deletion/mutagenesis reporter assays, and animal cap assays in Xenopus\",\n      \"pmids\": [\"36279927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo occupancy of the endogenous Pax8-CNS1 enhancer not shown by ChIP\", \"Selectivity over lhx1 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an upstream epigenetic regulator of MEIS3, showing HOXA1 deposits activating histone marks at the MEIS3 enhancer in hepatocellular carcinoma.\",\n      \"evidence\": \"ChIP assay and dual-luciferase reporter assay in HCC cells\",\n      \"pmids\": [\"33520978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method for the HOXA1-MEIS3 link\", \"Downstream MEIS3 effectors in HCC not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended MEIS3's enhancer-binding role to cancer, showing allele-specific binding to a regulatory variant that drives AGPS expression through a MEIS3/AGPS/NF-kB axis in esophageal carcinoma.\",\n      \"evidence\": \"CUT&Tag-qPCR, EMSA, RNAi, xenograft models, and Western blotting in ESCC cells\",\n      \"pmids\": [\"41950565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PBX/HOX partners participate at the AGPS variant not tested\", \"Mechanism linking AGPS to NF-kB activation not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MEIS3's binary versus trimeric PBX-HOX complex composition selects between activator and repressor outputs at distinct target enhancers remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MEIS3 on DNA with partners\", \"Genome-wide direct binding map not established\", \"Rules governing context-dependent activation versus repression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 10, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 4, 8, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 8]}\n    ],\n    \"complexes\": [\n      \"Pbx4-Meis3-Hoxb1b trimeric complex\",\n      \"Meis3-Tsh1 repressive complex\"\n    ],\n    \"partners\": [\n      \"PBX4\",\n      \"PBX1\",\n      \"HOXB1B\",\n      \"HOXB4\",\n      \"TSH1\",\n      \"HOXA1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}