{"gene":"CSRP1","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1992,"finding":"Human cysteine-rich protein (hCRP/CSRP1) expression is induced as a primary response to serum in quiescent cells (Balb/c 3T3 and human fibroblasts), with a kinetic profile paralleling c-myc. The gene encodes a protein containing the LIM/double zinc-finger motif, placing it in a superfamily of developmentally critical proteins, and is widely and conservedly expressed across tissues.","method":"Northern blotting and serum stimulation of quiescent cells; gene structure analysis; cDNA characterization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct expression induction assay with defined kinetics; single lab, multiple methods","pmids":["1374386"],"is_preprint":false},{"year":1992,"finding":"The human CSRP (hCRP) gene is present as a single copy in the human genome and maps to chromosome 1q24-1q32. Mouse and human genomes contain one or more CRP-related genes detectable by low-stringency hybridization.","method":"Somatic cell hybrid panel mapping; in situ hybridization to metaphase chromosomes; Southern blotting","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1-2 — direct chromosomal mapping with orthogonal methods (somatic cell hybrids + in situ hybridization)","pmids":["1385304"],"is_preprint":false},{"year":1994,"finding":"The LIM/double zinc-finger domain of human CSRP1 (hCRP) mediates efficient homodimerization. A single minimal LIM domain segment, when fused to an unrelated protein, is sufficient to confer dimerization ability. Dimerization occurs in vitro and in cells, in the absence or presence of DNA, and depends on coordination of two zinc atoms within the finger doublet.","method":"In vitro protein-protein interaction assays; cell-based dimerization studies; domain deletion and fusion constructs; zinc chelation experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro and validated in cells with mutagenesis/domain mapping; replicated with orthogonal approaches in single rigorous study","pmids":["7938009"],"is_preprint":false},{"year":2007,"finding":"Zebrafish Csrp1 physically interacts with Dishevelled 2 (Dvl2) and Diversin, components of the noncanonical Wnt/PCP pathway. Morpholino-mediated knockdown of csrp1 causes defective convergent extension cell movements in the mesendoderm and cardiac mesoderm cell migration failure, leading to cardiac bifida, establishing Csrp1 as a key regulator of noncanonical Wnt pathway-mediated tissue morphogenesis.","method":"Co-immunoprecipitation (Csrp1–Dvl2, Csrp1–Diversin); morpholino knockdown in zebrafish; cell movement analysis; phenotypic readout (midline defects, cardiac bifida)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus genetic loss-of-function with defined cellular phenotypes in a vertebrate model; multiple orthogonal methods","pmids":["17592114"],"is_preprint":false},{"year":2008,"finding":"A 5.0 kb Csrp1 enhancer drives arterial smooth muscle-restricted Cre expression beginning at ~E10.0, with subsequent expression in restricted skeletal and nonvascular smooth muscle lineages, establishing that Csrp1 regulatory elements direct expression specifically to arterial smooth muscle cells during cardiovascular development.","method":"Transgenic Cre mouse line driven by Csrp1 enhancer; ROSA26R reporter recombination assay; ROSA26-eGFP-DTA ablation crosses; lineage tracing","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo lineage tracing with reporter; single lab but multiple genetic tools","pmids":["18327771"],"is_preprint":false},{"year":2017,"finding":"A heterozygous frameshift duplication in human CSRP1 (at protein position 154) dramatically abrogates its transcriptional activation activity over cardiac promoters (e.g., NPPA). The mutation differentially inhibits physical association of CSRP1 with its transcriptional partners SRF, GATA4, and TBX5. Additionally, CSRP1 physically interacts with TRPS1, and the respective mutations in each protein abrogate their partnership. This identifies CSRP1 as a transcriptional co-activator for cardiac gene programs.","method":"Targeted exome sequencing; in vitro transcriptional reporter assays (luciferase over cardiac promoters); co-immunoprecipitation (CSRP1–SRF, CSRP1–GATA4, CSRP1–TBX5, CSRP1–TRPS1); mutant vs. wild-type protein comparisons","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional transcriptional assay with defined mutation; single lab, multiple orthogonal methods","pmids":["29326753"],"is_preprint":false},{"year":2024,"finding":"CSRP1 mRNA stability is regulated by the METTL3/YTHDF1 m6A axis: METTL3-mediated m6A modification of CSRP1 mRNA is recognized and bound by YTHDF1, which prevents mRNA degradation. CSRP1 knockdown inhibits AML cell proliferation and glycolysis, while overexpression promotes cell survival, placing CSRP1 downstream of METTL3/YTHDF1 as a regulator of glycolytic metabolism in AML.","method":"RNA immunoprecipitation (RIP); RNA stability assays; qRT-PCR; Western blotting; CSRP1 knockdown/overexpression with cell viability and glycolysis functional assays","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 — RIP and RNA stability assay with functional KD/OE readout; single lab, multiple methods","pmids":["39565517"],"is_preprint":false},{"year":2025,"finding":"Ectopic CSRP1 expression in MYCN-amplified neuroblastoma cells promotes neurite extension, enhances differentiation, increases apoptotic sensitivity (engaging both intrinsic caspase-9 and extrinsic caspase-8 pathways in a mitochondrial DNA-dependent manner), and upregulates innate immune receptor RIG-I. In mitochondrial DNA-depleted cells, CSRP1 upregulation does not activate caspase-9, indicating that CSRP1 channels apoptosis through the intrinsic pathway only when functional mitochondria are present.","method":"Ectopic CSRP1 overexpression; xenograft experiments with DAC/Poly(I:C) treatment; caspase-8 and caspase-9 activation assays; comparison between parental and mitochondrial DNA-depleted (ρ0) cells; neurite extension morphological analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — defined functional phenotypes with mechanistic pathway dissection using ρ0 cells; single lab, orthogonal in vitro and in vivo assays","pmids":["40198006"],"is_preprint":false},{"year":2025,"finding":"CSRP1 overexpression in renal cell carcinoma cells downregulates PD-L1 expression, inhibits proliferation and migration, and enhances sensitivity to sunitinib. In vivo, CSRP1 overexpression reduces tumor growth and improves response to anti-PD-L1 therapy in a mouse xenograft model, mechanistically linking CSRP1 to immune checkpoint regulation via PD-L1 suppression.","method":"CSRP1 overexpression in A498 and Renca cells; CCK-8 proliferation assay; wound healing migration assay; flow cytometry (apoptosis); qRT-PCR for PD-L1; BALB/c mouse xenograft with anti-PD-L1 antibody treatment","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression with multiple orthogonal functional assays plus in vivo validation; single lab","pmids":["41351404"],"is_preprint":false}],"current_model":"CSRP1 is a LIM/double zinc-finger domain protein that homodimerizes via its LIM domains, acts as a transcriptional co-activator for cardiac gene programs (interacting with SRF, GATA4, TBX5, and TRPS1), regulates noncanonical Wnt pathway-mediated convergent extension and cardiac mesoderm migration through interactions with Dishevelled 2 and Diversin, has its mRNA stability controlled by METTL3/YTHDF1-mediated m6A modification, and modulates apoptosis (via both intrinsic and extrinsic caspase pathways), differentiation, glycolysis, and PD-L1 expression in cancer contexts."},"narrative":{"teleology":[{"year":1992,"claim":"Identification of CSRP1 as a serum-responsive LIM-domain gene mapped to human chromosome 1q24-1q32 established it as a widely expressed, immediate-early gene belonging to a developmentally important protein superfamily.","evidence":"Northern blotting of serum-stimulated fibroblasts; somatic cell hybrid and in situ hybridization chromosome mapping","pmids":["1374386","1385304"],"confidence":"Medium","gaps":["Functional role beyond expression induction unknown","No protein-level interaction data at this stage","Tissue-specific function not addressed"]},{"year":1994,"claim":"Demonstrating that the LIM domain is both necessary and sufficient for zinc-dependent homodimerization resolved how CSRP1 self-associates and established the LIM domain as an autonomous protein–protein interaction module.","evidence":"In vitro binding assays with domain deletions and fusions; zinc chelation experiments; cell-based dimerization","pmids":["7938009"],"confidence":"High","gaps":["Heteromeric binding partners not yet identified","Functional consequence of dimerization unclear","No structural model of the dimer"]},{"year":2007,"claim":"Placing CSRP1 within the noncanonical Wnt/PCP pathway through physical interactions with Dishevelled 2 and Diversin, and showing that its loss causes convergent extension and cardiac migration defects, answered how CSRP1 contributes to tissue morphogenesis in vivo.","evidence":"Reciprocal Co-IP of Csrp1 with Dvl2 and Diversin; morpholino knockdown in zebrafish with phenotypic analysis","pmids":["17592114"],"confidence":"High","gaps":["Mammalian in vivo validation of PCP role missing","Domain mapping of Dvl2/Diversin interaction not reported","Downstream signaling effectors not identified"]},{"year":2008,"claim":"Identification of a 5.0 kb Csrp1 enhancer that drives arterial smooth muscle–restricted expression from E10.0 onward defined the spatial and temporal context for CSRP1 function during cardiovascular development.","evidence":"Transgenic Cre/ROSA26R lineage tracing in mouse with Csrp1 enhancer","pmids":["18327771"],"confidence":"Medium","gaps":["Endogenous Csrp1 protein expression pattern not independently confirmed by immunohistochemistry","Functional requirement in smooth muscle not tested by enhancer deletion"]},{"year":2017,"claim":"Demonstrating that CSRP1 physically interacts with SRF, GATA4, TBX5, and TRPS1 and co-activates cardiac promoters — and that a human frameshift mutation disrupts these interactions — established CSRP1 as a transcriptional co-activator for cardiac gene programs.","evidence":"Co-immunoprecipitation with wild-type and mutant CSRP1; luciferase reporter assays over NPPA promoter; targeted exome sequencing","pmids":["29326753"],"confidence":"Medium","gaps":["No chromatin-level evidence (ChIP) for CSRP1 occupancy at target promoters","Pathogenicity of the frameshift variant not confirmed in family segregation or animal model","Genome-wide transcriptional targets unknown"]},{"year":2024,"claim":"Revealing that METTL3-mediated m6A modification of CSRP1 mRNA is read by YTHDF1 to stabilize the transcript, and that CSRP1 sustains glycolysis and proliferation in AML, uncovered an epitranscriptomic layer of CSRP1 regulation and a pro-survival role in leukemia.","evidence":"RNA immunoprecipitation; RNA stability assays; CSRP1 knockdown/overexpression with glycolysis and viability readouts in AML cells","pmids":["39565517"],"confidence":"Medium","gaps":["Direct m6A site on CSRP1 mRNA not mapped at single-nucleotide resolution","Glycolytic targets downstream of CSRP1 not identified","Findings limited to AML cell lines"]},{"year":2025,"claim":"Showing that CSRP1 promotes neuroblastoma differentiation and apoptosis through mitochondrial DNA-dependent caspase-9 activation alongside caspase-8 engagement, and separately suppresses PD-L1 to enhance anti-tumor immunity in renal cell carcinoma, broadened CSRP1's role to differentiation, apoptosis, and immune checkpoint regulation in cancer.","evidence":"Ectopic expression in neuroblastoma with ρ0 cell controls and caspase assays; overexpression in RCC cells with PD-L1 qRT-PCR, flow cytometry, and mouse xenograft anti-PD-L1 treatment","pmids":["40198006","41351404"],"confidence":"Medium","gaps":["Mechanism by which CSRP1 regulates PD-L1 transcription is unknown","RIG-I upregulation pathway not delineated","Cancer phenotypes rely on overexpression without genetic loss-of-function confirmation"]},{"year":null,"claim":"The direct transcriptional targets of CSRP1, its chromatin-level occupancy, and the structural basis of its interactions with SRF/GATA4/TBX5 remain uncharacterized; how CSRP1 simultaneously participates in Wnt/PCP signaling and transcriptional co-activation, and whether these represent context-dependent or simultaneous functions, is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ChIP-seq or genome-wide binding data","No crystal or cryo-EM structure of CSRP1 in complex with any partner","Dual signaling-adaptor vs. transcriptional co-activator roles not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":[],"partners":["SRF","GATA4","TBX5","TRPS1","DVL2","ANKRD6","YTHDF1","METTL3"],"other_free_text":[]},"mechanistic_narrative":"CSRP1 is a LIM/double zinc-finger domain protein that functions as a transcriptional co-activator and signaling adaptor in cardiovascular development, differentiation, and cancer biology. Its LIM domains mediate zinc-dependent homodimerization and physical interactions with transcription factors SRF, GATA4, TBX5, and TRPS1 to co-activate cardiac gene programs such as the NPPA promoter, while interaction with Dishevelled 2 and Diversin couples CSRP1 to noncanonical Wnt/PCP signaling required for convergent extension and cardiac mesoderm migration [PMID:7938009, PMID:29326753, PMID:17592114]. CSRP1 mRNA stability is controlled by METTL3/YTHDF1-mediated m6A modification, and CSRP1 promotes glycolysis and cell survival in acute myeloid leukemia, while in neuroblastoma it drives differentiation, neurite extension, and apoptotic sensitivity through both intrinsic (caspase-9, mitochondrial DNA-dependent) and extrinsic (caspase-8) pathways [PMID:39565517, PMID:40198006]. In renal cell carcinoma, CSRP1 overexpression suppresses PD-L1, inhibits proliferation, and enhances responses to anti-PD-L1 immunotherapy in vivo [PMID:41351404]."},"prefetch_data":{"uniprot":{"accession":"P21291","full_name":"Cysteine and glycine-rich protein 1","aliases":["Cysteine-rich protein 1","CRP","CRP1","Epididymis luminal protein 141","HEL-141"],"length_aa":193,"mass_kda":20.6,"function":"Could play a role in neuronal development","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P21291/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CSRP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSPA8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CSRP1","total_profiled":1310},"omim":[{"mim_id":"614215","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 1; ASCC1","url":"https://www.omim.org/entry/614215"},{"mim_id":"604501","title":"THYROID HORMONE RECEPTOR INTERACTOR 4; TRIP4","url":"https://www.omim.org/entry/604501"},{"mim_id":"601871","title":"CYSTEINE- AND GLYCINE-RICH PROTEIN 2; CSRP2","url":"https://www.omim.org/entry/601871"},{"mim_id":"601183","title":"CYSTEINE-RICH INTESTINAL PROTEIN 2; CRIP2","url":"https://www.omim.org/entry/601183"},{"mim_id":"123876","title":"CYSTEINE- AND GLYCINE-RICH PROTEIN 1; CSRP1","url":"https://www.omim.org/entry/123876"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":2631.0},{"tissue":"intestine","ntpm":2839.1}],"url":"https://www.proteinatlas.org/search/CSRP1"},"hgnc":{"alias_symbol":["CSRP","D1S181E"],"prev_symbol":["CYRP"]},"alphafold":{"accession":"P21291","domains":[{"cath_id":"2.10.110.10","chopping":"21-65","consensus_level":"high","plddt":85.2687,"start":21,"end":65},{"cath_id":"2.10.110.10","chopping":"130-174","consensus_level":"high","plddt":83.2678,"start":130,"end":174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21291","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21291-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21291-F1-predicted_aligned_error_v6.png","plddt_mean":71.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CSRP1","jax_strain_url":"https://www.jax.org/strain/search?query=CSRP1"},"sequence":{"accession":"P21291","fasta_url":"https://rest.uniprot.org/uniprotkb/P21291.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21291/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21291"}},"corpus_meta":[{"pmid":"17592114","id":"PMC_17592114","title":"Csrp1 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signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20029029","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30397336","id":"PMC_30397336","title":"Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens.","date":"2018","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30397336","citation_count":146,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21832049","id":"PMC_21832049","title":"Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832049","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24457600","id":"PMC_24457600","title":"The central role of EED in the orchestration of polycomb group complexes.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24457600","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17486081","id":"PMC_17486081","title":"Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17486081","citation_count":117,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35013218","id":"PMC_35013218","title":"EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013218","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1374386","id":"PMC_1374386","title":"Human cysteine-rich protein. A member of the LIM/double-finger family displaying coordinate serum induction with c-myc.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1374386","citation_count":97,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8163,"output_tokens":1727,"usd":0.025197},"stage2":{"model":"claude-opus-4-6","input_tokens":4982,"output_tokens":1806,"usd":0.10509},"total_usd":0.409652,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":19783,"output_tokens":3832,"usd":0.058415},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6190,"output_tokens":4654,"usd":0.22095}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Zebrafish Csrp1 (ortholog of mammalian CSRP1) physically interacts with Dishevelled 2 (Dvl2) and Diversin, placing it in the noncanonical Wnt/JNK pathway; knockdown of csrp1 causes defective convergent extension cell movements and cardiac bifida due to failed cardiac mesoderm migration.\",\n      \"method\": \"Co-immunoprecipitation/interaction studies, morpholino knockdown in zebrafish with phenotypic analysis of cell movement and cardiac morphogenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interactions demonstrated and clean KD with defined cellular phenotype, single lab\",\n      \"pmids\": [\"17592114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A frameshift mutation in human CSRP1 dramatically abrogates its transcriptional activity over cardiac promoters (e.g., NPPA) and differentially inhibits its physical association with SRF, GATA4, and TBX5; CSRP1 also physically interacts with TRPS1, and mutations in each abrogate their partnership.\",\n      \"method\": \"In vitro transcriptional reporter assays, co-immunoprecipitation, targeted exome sequencing with segregation analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding partners confirmed by Co-IP and functional transcription assays, single lab\",\n      \"pmids\": [\"29326753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Human CSRP1 (hCRP) encodes a protein with two LIM/double zinc-finger motifs, is a single-copy gene mapped to chromosome 1q24-1q32, and is a serum-inducible immediate early response gene.\",\n      \"method\": \"Southern blotting, somatic cell hybrid panel mapping, in situ hybridization, cDNA characterization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping and domain identification by sequence/hybridization, single study\",\n      \"pmids\": [\"1385304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A 5.0 kb Csrp1 enhancer drives arterial smooth muscle cell-specific Cre expression beginning at ~E10.0, and Csrp1-expressing lineages subsequently contribute to restricted skeletal and nonvascular smooth muscle lineages, defining Csrp1 as a marker of the smooth muscle lineage.\",\n      \"method\": \"Transgenic Cre mouse line with ROSA26R reporter for lineage tracing and diphtheria toxin-mediated cell ablation\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct lineage tracing with reporter and ablation, single lab\",\n      \"pmids\": [\"18327771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 enhances CSRP1 mRNA stability via m6A modification, which is recognized and bound by YTHDF1, preventing CSRP1 mRNA degradation; knockdown of CSRP1 inhibits AML cell proliferation and glycolysis, while overexpression promotes survival.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA stability assays, qRT-PCR, Western blotting, functional cell viability and glycolysis assays with CSRP1 KD/OE\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and RNA stability assays establish m6A-mediated mechanism, with functional KD/OE validation, single lab\",\n      \"pmids\": [\"39565517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of CSRP1 in renal cell carcinoma cells downregulates PD-L1 expression, inhibits proliferation and migration, and enhances sensitivity to sunitinib; in vivo, CSRP1 overexpression reduces tumor growth and improves response to anti-PD-L1 therapy.\",\n      \"method\": \"qRT-PCR, CCK-8, wound healing, flow cytometry, xenograft mouse model with anti-PD-L1 treatment\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic link to PD-L1 downregulation shown by expression assay only, no direct molecular interaction demonstrated\",\n      \"pmids\": [\"41351404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSRP1 expression in neuroblastoma promotes neurite extension, differentiation, and apoptosis; ectopic CSRP1 activates both intrinsic (caspase-9) and extrinsic (caspase-8) apoptosis pathways in a mitochondrial DNA-dependent manner, and is associated with RIG-I upregulation.\",\n      \"method\": \"Ectopic CSRP1 overexpression in BE(2)-M17 and SK-N-AS cells, xenograft models, caspase activity assays, mitochondrial DNA-depleted (ρ0) cell comparisons\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional phenotype and pathway placement by caspase assays, but molecular mechanism linking CSRP1 to apoptosis machinery not directly established\",\n      \"pmids\": [\"40198006\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSRP1 is a LIM/double zinc-finger domain protein that acts as a transcriptional co-activator (interacting with SRF, GATA4, TBX5) in cardiac development, interacts with Dishevelled and Diversin to regulate noncanonical Wnt/JNK-dependent cell movements in mesendoderm and cardiac mesoderm, marks and is required for arterial smooth muscle cell identity, and has its mRNA stability regulated by METTL3/YTHDF1-mediated m6A modification to promote glycolysis in AML cells.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- [1] PMID:17592114 — KEEP (zebrafish Csrp1 ortholog, consistent domain architecture and cellular context)\n- [2] PMID:28395772 — EXCLUDE (alias collision: CSRP = \"circular strand-replacement DNA polymerization\", not the gene)\n- [3] PMID:19634002 — EXCLUDE (about CSRP3, not CSRP1; comparative mention only, no mechanistic findings about CSRP1)\n- [4] PMID:1385304 — KEEP (human CSRP1 gene characterization)\n- [5] PMID:18327771 — KEEP (mouse Csrp1 enhancer/Cre line, smooth muscle expression)\n- [6] PMID:23537997 — EXCLUDE (association/SNV study, no mechanism)\n- [7] PMID:29326753 — KEEP (human CSRP1 mutation, mechanistic characterization of protein interactions)\n- [8] PMID:39565517 — KEEP (METTL3/YTHDF1 regulation of CSRP1 mRNA)\n- [9] PMID:40198006 — KEEP (CSRP1 role in neuroblastoma differentiation/apoptosis)\n- [10] PMID:39994616 — EXCLUDE (biomarker/prognostic study, no new mechanism)\n- [11] PMID:41707204 — EXCLUDE (alias collision: CSRP here = Cu-only SOD repeat proteins, fundamentally different protein)\n- [12] PMID:41398130 — EXCLUDE (computational/expression study, no direct mechanism)\n- [13] PMID:41351404 — KEEP (CSRP1 overexpression mechanistic study in RCC)\n- [14] bio_10.1101_2025.03.31.25324765 — EXCLUDE (about CSRP1-AS1 lncRNA, alt-locus product)\n\n**Gene2pubmed additional papers:**\n- PMID:17081983 — EXCLUDE (large phosphoproteomics dataset, no specific CSRP1 mechanism)\n- PMID:22658674 — EXCLUDE (mRNA interactome atlas, no specific CSRP1 mechanism)\n- PMID:12477932 — EXCLUDE (cDNA collection resource)\n- PMID:16964243 — EXCLUDE (phosphoproteomics method)\n- PMID:32296183 — EXCLUDE (general interactome map)\n- PMID:11790298 — EXCLUDE (nucleolar proteomics)\n- PMID:14702039 — EXCLUDE (cDNA collection)\n- PMID:33961781 — EXCLUDE (general interactome)\n- PMID:21873635 — EXCLUDE (GO annotation method)\n- PMID:19056867 — EXCLUDE (urinary exosome proteomics)\n- PMID:21423176 — EXCLUDE (focal adhesion proteomics)\n- PMID:15489334 — EXCLUDE (MGC resource)\n- PMID:26638075 — EXCLUDE (centrosome proteomics)\n- PMID:35271311 — EXCLUDE (general proteome map)\n- PMID:16344560 — EXCLUDE (alternative promoters resource)\n- PMID:26344197 — EXCLUDE (metazoan complexes resource)\n- PMID:22863883 — EXCLUDE (interactome method)\n- PMID:35063084 — EXCLUDE (Tau interactome)\n- PMID:29568061 — EXCLUDE (MAC-tag method)\n- PMID:20029029 — EXCLUDE (EGFR/HDAC6 study)\n- PMID:30397336 — EXCLUDE (phagocytosis CRISPR screen)\n- PMID:21832049 — EXCLUDE (TPPP/p25 study)\n- PMID:24457600 — EXCLUDE (EED/PRC study)\n- PMID:23376485 — EXCLUDE (podocyte exosome proteomics)\n- PMID:17486081 — EXCLUDE (alias collision: CRIP1 = cysteine-rich intestinal protein 1, different gene from CSRP1)\n- PMID:20379614 — EXCLUDE (smoking cessation genetics)\n- PMID:35013218 — EXCLUDE (EZH2/MYC study)\n- PMID:7938009 — KEEP (hCRP/CSRP1 LIM domain dimerization mechanism)\n- PMID:1374386 — KEEP (human CRP/CSRP1 serum induction and LIM characterization)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"Human cysteine-rich protein (hCRP/CSRP1) expression is induced as a primary response to serum in quiescent cells (Balb/c 3T3 and human fibroblasts), with a kinetic profile paralleling c-myc. The gene encodes a protein containing the LIM/double zinc-finger motif, placing it in a superfamily of developmentally critical proteins, and is widely and conservedly expressed across tissues.\",\n      \"method\": \"Northern blotting and serum stimulation of quiescent cells; gene structure analysis; cDNA characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct expression induction assay with defined kinetics; single lab, multiple methods\",\n      \"pmids\": [\"1374386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human CSRP (hCRP) gene is present as a single copy in the human genome and maps to chromosome 1q24-1q32. Mouse and human genomes contain one or more CRP-related genes detectable by low-stringency hybridization.\",\n      \"method\": \"Somatic cell hybrid panel mapping; in situ hybridization to metaphase chromosomes; Southern blotting\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct chromosomal mapping with orthogonal methods (somatic cell hybrids + in situ hybridization)\",\n      \"pmids\": [\"1385304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The LIM/double zinc-finger domain of human CSRP1 (hCRP) mediates efficient homodimerization. A single minimal LIM domain segment, when fused to an unrelated protein, is sufficient to confer dimerization ability. Dimerization occurs in vitro and in cells, in the absence or presence of DNA, and depends on coordination of two zinc atoms within the finger doublet.\",\n      \"method\": \"In vitro protein-protein interaction assays; cell-based dimerization studies; domain deletion and fusion constructs; zinc chelation experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro and validated in cells with mutagenesis/domain mapping; replicated with orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"7938009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Zebrafish Csrp1 physically interacts with Dishevelled 2 (Dvl2) and Diversin, components of the noncanonical Wnt/PCP pathway. Morpholino-mediated knockdown of csrp1 causes defective convergent extension cell movements in the mesendoderm and cardiac mesoderm cell migration failure, leading to cardiac bifida, establishing Csrp1 as a key regulator of noncanonical Wnt pathway-mediated tissue morphogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Csrp1–Dvl2, Csrp1–Diversin); morpholino knockdown in zebrafish; cell movement analysis; phenotypic readout (midline defects, cardiac bifida)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus genetic loss-of-function with defined cellular phenotypes in a vertebrate model; multiple orthogonal methods\",\n      \"pmids\": [\"17592114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A 5.0 kb Csrp1 enhancer drives arterial smooth muscle-restricted Cre expression beginning at ~E10.0, with subsequent expression in restricted skeletal and nonvascular smooth muscle lineages, establishing that Csrp1 regulatory elements direct expression specifically to arterial smooth muscle cells during cardiovascular development.\",\n      \"method\": \"Transgenic Cre mouse line driven by Csrp1 enhancer; ROSA26R reporter recombination assay; ROSA26-eGFP-DTA ablation crosses; lineage tracing\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo lineage tracing with reporter; single lab but multiple genetic tools\",\n      \"pmids\": [\"18327771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A heterozygous frameshift duplication in human CSRP1 (at protein position 154) dramatically abrogates its transcriptional activation activity over cardiac promoters (e.g., NPPA). The mutation differentially inhibits physical association of CSRP1 with its transcriptional partners SRF, GATA4, and TBX5. Additionally, CSRP1 physically interacts with TRPS1, and the respective mutations in each protein abrogate their partnership. This identifies CSRP1 as a transcriptional co-activator for cardiac gene programs.\",\n      \"method\": \"Targeted exome sequencing; in vitro transcriptional reporter assays (luciferase over cardiac promoters); co-immunoprecipitation (CSRP1–SRF, CSRP1–GATA4, CSRP1–TBX5, CSRP1–TRPS1); mutant vs. wild-type protein comparisons\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional transcriptional assay with defined mutation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29326753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CSRP1 mRNA stability is regulated by the METTL3/YTHDF1 m6A axis: METTL3-mediated m6A modification of CSRP1 mRNA is recognized and bound by YTHDF1, which prevents mRNA degradation. CSRP1 knockdown inhibits AML cell proliferation and glycolysis, while overexpression promotes cell survival, placing CSRP1 downstream of METTL3/YTHDF1 as a regulator of glycolytic metabolism in AML.\",\n      \"method\": \"RNA immunoprecipitation (RIP); RNA stability assays; qRT-PCR; Western blotting; CSRP1 knockdown/overexpression with cell viability and glycolysis functional assays\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and RNA stability assay with functional KD/OE readout; single lab, multiple methods\",\n      \"pmids\": [\"39565517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ectopic CSRP1 expression in MYCN-amplified neuroblastoma cells promotes neurite extension, enhances differentiation, increases apoptotic sensitivity (engaging both intrinsic caspase-9 and extrinsic caspase-8 pathways in a mitochondrial DNA-dependent manner), and upregulates innate immune receptor RIG-I. In mitochondrial DNA-depleted cells, CSRP1 upregulation does not activate caspase-9, indicating that CSRP1 channels apoptosis through the intrinsic pathway only when functional mitochondria are present.\",\n      \"method\": \"Ectopic CSRP1 overexpression; xenograft experiments with DAC/Poly(I:C) treatment; caspase-8 and caspase-9 activation assays; comparison between parental and mitochondrial DNA-depleted (ρ0) cells; neurite extension morphological analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined functional phenotypes with mechanistic pathway dissection using ρ0 cells; single lab, orthogonal in vitro and in vivo assays\",\n      \"pmids\": [\"40198006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSRP1 overexpression in renal cell carcinoma cells downregulates PD-L1 expression, inhibits proliferation and migration, and enhances sensitivity to sunitinib. In vivo, CSRP1 overexpression reduces tumor growth and improves response to anti-PD-L1 therapy in a mouse xenograft model, mechanistically linking CSRP1 to immune checkpoint regulation via PD-L1 suppression.\",\n      \"method\": \"CSRP1 overexpression in A498 and Renca cells; CCK-8 proliferation assay; wound healing migration assay; flow cytometry (apoptosis); qRT-PCR for PD-L1; BALB/c mouse xenograft with anti-PD-L1 antibody treatment\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with multiple orthogonal functional assays plus in vivo validation; single lab\",\n      \"pmids\": [\"41351404\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSRP1 is a LIM/double zinc-finger domain protein that homodimerizes via its LIM domains, acts as a transcriptional co-activator for cardiac gene programs (interacting with SRF, GATA4, TBX5, and TRPS1), regulates noncanonical Wnt pathway-mediated convergent extension and cardiac mesoderm migration through interactions with Dishevelled 2 and Diversin, has its mRNA stability controlled by METTL3/YTHDF1-mediated m6A modification, and modulates apoptosis (via both intrinsic and extrinsic caspase pathways), differentiation, glycolysis, and PD-L1 expression in cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CSRP1 is a LIM/double zinc-finger domain protein that functions as a transcriptional co-activator and signaling scaffold in cardiovascular development and smooth muscle cell identity. Encoded as a serum-inducible immediate early gene on chromosome 1q24-1q32, CSRP1 physically interacts with the cardiac transcription factors SRF, GATA4, TBX5, and TRPS1 to co-activate cardiac gene promoters, and a human frameshift mutation abrogates this transcriptional activity [PMID:1385304, PMID:29326753]. CSRP1 also operates in the noncanonical Wnt/JNK pathway through physical interaction with Dishevelled 2 and Diversin, and its loss in zebrafish causes convergent extension defects and cardiac bifida due to failed cardiac mesoderm migration [PMID:17592114]. In mice, Csrp1 marks the arterial smooth muscle cell lineage from ~E10.0 and its expression domain extends to restricted skeletal and nonvascular smooth muscle populations [PMID:18327771].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"The molecular identity of CSRP1 was established as a single-copy, serum-inducible immediate early gene encoding two LIM/double zinc-finger motifs, defining the protein as a potential transcriptional or signaling adaptor.\",\n      \"evidence\": \"Southern blotting, somatic cell hybrid panel mapping, in situ hybridization, and cDNA characterization in human cells\",\n      \"pmids\": [\"1385304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay for the protein was performed\",\n        \"Binding partners for the LIM domains were unknown\",\n        \"Tissue-specific roles not addressed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CSRP1 was placed in the noncanonical Wnt/JNK pathway via direct interaction with Dvl2 and Diversin, and its requirement for convergent extension cell movements and cardiac mesoderm migration was demonstrated, establishing a cell-biological function beyond transcription.\",\n      \"evidence\": \"Co-immunoprecipitation of Csrp1 with Dvl2 and Diversin, morpholino knockdown in zebrafish with phenotypic analysis\",\n      \"pmids\": [\"17592114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mammalian in vivo confirmation of the Wnt/JNK role not performed\",\n        \"Domains mediating the Dvl2/Diversin interaction not mapped\",\n        \"Downstream JNK substrates linking CSRP1 to cell polarity not identified\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Lineage tracing showed that Csrp1-expressing progenitors contribute specifically to arterial smooth muscle and restricted skeletal/nonvascular smooth muscle populations, establishing CSRP1 as a lineage marker for smooth muscle identity.\",\n      \"evidence\": \"Transgenic Csrp1-Cre mouse line with ROSA26R reporter and diphtheria toxin-mediated ablation\",\n      \"pmids\": [\"18327771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CSRP1 is functionally required for smooth muscle differentiation was not tested by gene knockout\",\n        \"Regulatory inputs controlling the Csrp1 enhancer not characterized\",\n        \"Relationship between smooth muscle and cardiac roles of CSRP1 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CSRP1 was shown to function as a transcriptional co-activator on cardiac promoters through physical partnerships with SRF, GATA4, TBX5, and TRPS1; a human frameshift mutation abrogated transcriptional activity and differentially disrupted these interactions, linking CSRP1 variants to cardiac gene regulation.\",\n      \"evidence\": \"In vitro transcriptional reporter assays, co-immunoprecipitation, targeted exome sequencing with segregation analysis\",\n      \"pmids\": [\"29326753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide co-activator binding sites not determined\",\n        \"Structural basis for differential partner disruption by the frameshift not resolved\",\n        \"Clinical significance of the CSRP1 mutation in cardiomyopathy not established in independent cohorts\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CSRP1 mRNA stability was shown to be regulated by METTL3-mediated m6A modification read by YTHDF1, and CSRP1 itself promotes AML cell proliferation and glycolysis, revealing a post-transcriptional regulatory axis and an oncogenic role in leukemia.\",\n      \"evidence\": \"RNA immunoprecipitation, RNA stability assays, CSRP1 knockdown and overexpression with glycolysis and viability assays in AML cells\",\n      \"pmids\": [\"39565517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular targets of CSRP1 in glycolysis regulation not identified\",\n        \"Whether the m6A-dependent mechanism operates in normal hematopoietic cells unknown\",\n        \"In vivo AML model validation not provided\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism by which CSRP1 integrates its transcription co-activator and Wnt/JNK signaling functions, and whether its roles in smooth muscle identity, cardiac development, and oncogenesis reflect a unified or context-specific mechanism, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CSRP1 in complex with any partner exists\",\n        \"Conditional knockout in mammalian cardiac and smooth muscle tissues has not been reported\",\n        \"Genome-wide identification of CSRP1-dependent transcriptional targets is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DVL2\",\n      \"ANKRD6\",\n      \"SRF\",\n      \"GATA4\",\n      \"TBX5\",\n      \"TRPS1\",\n      \"YTHDF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CSRP1 is a LIM/double zinc-finger domain protein that functions as a transcriptional co-activator and signaling adaptor in cardiovascular development, differentiation, and cancer biology. Its LIM domains mediate zinc-dependent homodimerization and physical interactions with transcription factors SRF, GATA4, TBX5, and TRPS1 to co-activate cardiac gene programs such as the NPPA promoter, while interaction with Dishevelled 2 and Diversin couples CSRP1 to noncanonical Wnt/PCP signaling required for convergent extension and cardiac mesoderm migration [PMID:7938009, PMID:29326753, PMID:17592114]. CSRP1 mRNA stability is controlled by METTL3/YTHDF1-mediated m6A modification, and CSRP1 promotes glycolysis and cell survival in acute myeloid leukemia, while in neuroblastoma it drives differentiation, neurite extension, and apoptotic sensitivity through both intrinsic (caspase-9, mitochondrial DNA-dependent) and extrinsic (caspase-8) pathways [PMID:39565517, PMID:40198006]. In renal cell carcinoma, CSRP1 overexpression suppresses PD-L1, inhibits proliferation, and enhances responses to anti-PD-L1 immunotherapy in vivo [PMID:41351404].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of CSRP1 as a serum-responsive LIM-domain gene mapped to human chromosome 1q24-1q32 established it as a widely expressed, immediate-early gene belonging to a developmentally important protein superfamily.\",\n      \"evidence\": \"Northern blotting of serum-stimulated fibroblasts; somatic cell hybrid and in situ hybridization chromosome mapping\",\n      \"pmids\": [\"1374386\", \"1385304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role beyond expression induction unknown\", \"No protein-level interaction data at this stage\", \"Tissue-specific function not addressed\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that the LIM domain is both necessary and sufficient for zinc-dependent homodimerization resolved how CSRP1 self-associates and established the LIM domain as an autonomous protein–protein interaction module.\",\n      \"evidence\": \"In vitro binding assays with domain deletions and fusions; zinc chelation experiments; cell-based dimerization\",\n      \"pmids\": [\"7938009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromeric binding partners not yet identified\", \"Functional consequence of dimerization unclear\", \"No structural model of the dimer\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placing CSRP1 within the noncanonical Wnt/PCP pathway through physical interactions with Dishevelled 2 and Diversin, and showing that its loss causes convergent extension and cardiac migration defects, answered how CSRP1 contributes to tissue morphogenesis in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP of Csrp1 with Dvl2 and Diversin; morpholino knockdown in zebrafish with phenotypic analysis\",\n      \"pmids\": [\"17592114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian in vivo validation of PCP role missing\", \"Domain mapping of Dvl2/Diversin interaction not reported\", \"Downstream signaling effectors not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of a 5.0 kb Csrp1 enhancer that drives arterial smooth muscle–restricted expression from E10.0 onward defined the spatial and temporal context for CSRP1 function during cardiovascular development.\",\n      \"evidence\": \"Transgenic Cre/ROSA26R lineage tracing in mouse with Csrp1 enhancer\",\n      \"pmids\": [\"18327771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous Csrp1 protein expression pattern not independently confirmed by immunohistochemistry\", \"Functional requirement in smooth muscle not tested by enhancer deletion\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that CSRP1 physically interacts with SRF, GATA4, TBX5, and TRPS1 and co-activates cardiac promoters — and that a human frameshift mutation disrupts these interactions — established CSRP1 as a transcriptional co-activator for cardiac gene programs.\",\n      \"evidence\": \"Co-immunoprecipitation with wild-type and mutant CSRP1; luciferase reporter assays over NPPA promoter; targeted exome sequencing\",\n      \"pmids\": [\"29326753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No chromatin-level evidence (ChIP) for CSRP1 occupancy at target promoters\", \"Pathogenicity of the frameshift variant not confirmed in family segregation or animal model\", \"Genome-wide transcriptional targets unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing that METTL3-mediated m6A modification of CSRP1 mRNA is read by YTHDF1 to stabilize the transcript, and that CSRP1 sustains glycolysis and proliferation in AML, uncovered an epitranscriptomic layer of CSRP1 regulation and a pro-survival role in leukemia.\",\n      \"evidence\": \"RNA immunoprecipitation; RNA stability assays; CSRP1 knockdown/overexpression with glycolysis and viability readouts in AML cells\",\n      \"pmids\": [\"39565517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A site on CSRP1 mRNA not mapped at single-nucleotide resolution\", \"Glycolytic targets downstream of CSRP1 not identified\", \"Findings limited to AML cell lines\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that CSRP1 promotes neuroblastoma differentiation and apoptosis through mitochondrial DNA-dependent caspase-9 activation alongside caspase-8 engagement, and separately suppresses PD-L1 to enhance anti-tumor immunity in renal cell carcinoma, broadened CSRP1's role to differentiation, apoptosis, and immune checkpoint regulation in cancer.\",\n      \"evidence\": \"Ectopic expression in neuroblastoma with ρ0 cell controls and caspase assays; overexpression in RCC cells with PD-L1 qRT-PCR, flow cytometry, and mouse xenograft anti-PD-L1 treatment\",\n      \"pmids\": [\"40198006\", \"41351404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CSRP1 regulates PD-L1 transcription is unknown\", \"RIG-I upregulation pathway not delineated\", \"Cancer phenotypes rely on overexpression without genetic loss-of-function confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct transcriptional targets of CSRP1, its chromatin-level occupancy, and the structural basis of its interactions with SRF/GATA4/TBX5 remain uncharacterized; how CSRP1 simultaneously participates in Wnt/PCP signaling and transcriptional co-activation, and whether these represent context-dependent or simultaneous functions, is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP-seq or genome-wide binding data\", \"No crystal or cryo-EM structure of CSRP1 in complex with any partner\", \"Dual signaling-adaptor vs. transcriptional co-activator roles not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRF\", \"GATA4\", \"TBX5\", \"TRPS1\", \"DVL2\", \"ANKRD6\", \"YTHDF1\", \"METTL3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway entries — I accidentally included a GO term where only Reactome IDs are allowed. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"CSRP1 is a LIM/double zinc-finger domain protein that functions as a transcriptional co-activator and signaling adaptor in cardiovascular development, differentiation, and cancer biology. Its LIM domains mediate zinc-dependent homodimerization and physical interactions with transcription factors SRF, GATA4, TBX5, and TRPS1 to co-activate cardiac gene programs such as the NPPA promoter, while interaction with Dishevelled 2 and Diversin couples CSRP1 to noncanonical Wnt/PCP signaling required for convergent extension and cardiac mesoderm migration [PMID:7938009, PMID:29326753, PMID:17592114]. CSRP1 mRNA stability is controlled by METTL3/YTHDF1-mediated m6A modification, and CSRP1 promotes glycolysis and cell survival in acute myeloid leukemia, while in neuroblastoma it drives differentiation, neurite extension, and apoptotic sensitivity through both intrinsic (caspase-9, mitochondrial DNA-dependent) and extrinsic (caspase-8) pathways [PMID:39565517, PMID:40198006]. In renal cell carcinoma, CSRP1 overexpression suppresses PD-L1, inhibits proliferation, and enhances responses to anti-PD-L1 immunotherapy in vivo [PMID:41351404].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of CSRP1 as a serum-responsive LIM-domain gene mapped to human chromosome 1q24-1q32 established it as a widely expressed, immediate-early gene belonging to a developmentally important protein superfamily.\",\n      \"evidence\": \"Northern blotting of serum-stimulated fibroblasts; somatic cell hybrid and in situ hybridization chromosome mapping\",\n      \"pmids\": [\"1374386\", \"1385304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role beyond expression induction unknown\", \"No protein-level interaction data at this stage\", \"Tissue-specific function not addressed\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that the LIM domain is both necessary and sufficient for zinc-dependent homodimerization resolved how CSRP1 self-associates and established the LIM domain as an autonomous protein–protein interaction module.\",\n      \"evidence\": \"In vitro binding assays with domain deletions and fusions; zinc chelation experiments; cell-based dimerization\",\n      \"pmids\": [\"7938009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromeric binding partners not yet identified\", \"Functional consequence of dimerization unclear\", \"No structural model of the dimer\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placing CSRP1 within the noncanonical Wnt/PCP pathway through physical interactions with Dishevelled 2 and Diversin, and showing that its loss causes convergent extension and cardiac migration defects, answered how CSRP1 contributes to tissue morphogenesis in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP of Csrp1 with Dvl2 and Diversin; morpholino knockdown in zebrafish with phenotypic analysis\",\n      \"pmids\": [\"17592114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian in vivo validation of PCP role missing\", \"Domain mapping of Dvl2/Diversin interaction not reported\", \"Downstream signaling effectors not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of a 5.0 kb Csrp1 enhancer that drives arterial smooth muscle–restricted expression from E10.0 onward defined the spatial and temporal context for CSRP1 function during cardiovascular development.\",\n      \"evidence\": \"Transgenic Cre/ROSA26R lineage tracing in mouse with Csrp1 enhancer\",\n      \"pmids\": [\"18327771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous Csrp1 protein expression pattern not independently confirmed by immunohistochemistry\", \"Functional requirement in smooth muscle not tested by enhancer deletion\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that CSRP1 physically interacts with SRF, GATA4, TBX5, and TRPS1 and co-activates cardiac promoters — and that a human frameshift mutation disrupts these interactions — established CSRP1 as a transcriptional co-activator for cardiac gene programs.\",\n      \"evidence\": \"Co-immunoprecipitation with wild-type and mutant CSRP1; luciferase reporter assays over NPPA promoter; targeted exome sequencing\",\n      \"pmids\": [\"29326753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No chromatin-level evidence (ChIP) for CSRP1 occupancy at target promoters\", \"Pathogenicity of the frameshift variant not confirmed in family segregation or animal model\", \"Genome-wide transcriptional targets unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing that METTL3-mediated m6A modification of CSRP1 mRNA is read by YTHDF1 to stabilize the transcript, and that CSRP1 sustains glycolysis and proliferation in AML, uncovered an epitranscriptomic layer of CSRP1 regulation and a pro-survival role in leukemia.\",\n      \"evidence\": \"RNA immunoprecipitation; RNA stability assays; CSRP1 knockdown/overexpression with glycolysis and viability readouts in AML cells\",\n      \"pmids\": [\"39565517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A site on CSRP1 mRNA not mapped at single-nucleotide resolution\", \"Glycolytic targets downstream of CSRP1 not identified\", \"Findings limited to AML cell lines\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that CSRP1 promotes neuroblastoma differentiation and apoptosis through mitochondrial DNA-dependent caspase-9 activation alongside caspase-8 engagement, and separately suppresses PD-L1 to enhance anti-tumor immunity in renal cell carcinoma, broadened CSRP1's role to differentiation, apoptosis, and immune checkpoint regulation in cancer.\",\n      \"evidence\": \"Ectopic expression in neuroblastoma with ρ0 cell controls and caspase assays; overexpression in RCC cells with PD-L1 qRT-PCR, flow cytometry, and mouse xenograft anti-PD-L1 treatment\",\n      \"pmids\": [\"40198006\", \"41351404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CSRP1 regulates PD-L1 transcription is unknown\", \"RIG-I upregulation pathway not delineated\", \"Cancer phenotypes rely on overexpression without genetic loss-of-function confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct transcriptional targets of CSRP1, its chromatin-level occupancy, and the structural basis of its interactions with SRF/GATA4/TBX5 remain uncharacterized; how CSRP1 simultaneously participates in Wnt/PCP signaling and transcriptional co-activation, and whether these represent context-dependent or simultaneous functions, is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP-seq or genome-wide binding data\", \"No crystal or cryo-EM structure of CSRP1 in complex with any partner\", \"Dual signaling-adaptor vs. transcriptional co-activator roles not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRF\", \"GATA4\", \"TBX5\", \"TRPS1\", \"DVL2\", \"ANKRD6\", \"YTHDF1\", \"METTL3\"],\n    \"other_free_text\": []\n  }\n}\n```"}