{"gene":"DYNC1I1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2014,"finding":"Exons 15 and 17 of DYNC1I1 function as tissue-specific limb enhancers (exonic enhancers) that cis-regulate the expression of the adjacent genes DLX5 and DLX6 during limb development. Chromosomal rearrangements that separate these DYNC1I1 exons from DLX5/6, or deletions encompassing only these exons while leaving DLX5/6 disomic, cause split-hand/split-foot malformation in humans.","method":"Whole genome sequencing of chromosomal rearrangement breakpoints; copy number analysis via exome sequencing identifying 106 kb deletion removing DYNC1I1 exons 15/17 while DLX5/6 remain intact","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across two independent families in one paper (PMID:24459211) and confirmed in additional families by array CGH in a separate cohort study (PMID:25231166); orthogonal methods (WGS breakpoint mapping + CNV analysis) converge on the same mechanistic conclusion","pmids":["24459211","25231166"],"is_preprint":false},{"year":2019,"finding":"DYNC1I1 promotes gastric cancer cell proliferation and migration by upregulating IL-6 expression through increasing NF-κB nuclear translocation, thereby activating the IL-6/STAT signaling pathway.","method":"In vitro knockdown/overexpression assays (proliferation, migration), in vivo xenograft assays, NF-κB nuclear translocation assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype and pathway placement (NF-κB nuclear translocation measured), but single lab with no independent replication","pmids":["31249807"],"is_preprint":false},{"year":2019,"finding":"DYNC1I1 upregulates TNPO2 expression by upregulating the transcription factor SP1, which then recruits and binds to P300-acetylated histone regions at the TNPO2 promoter to drive TNPO2 transcription. TNPO2 in turn promotes gastric cancer cell proliferation and inhibits apoptosis, potentially via P21.","method":"Expression profile chip identifying TNPO2 as downstream target; mechanistic follow-up with transcription factor binding and promoter acetylation assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement established via expression chip and promoter assays in single lab; SP1/P300 mechanism described but relies on a single lab without independent replication","pmids":["31605449"],"is_preprint":false},{"year":2016,"finding":"DYNC1I1 deficiency in primary hippocampal neurons causes neuronal atrophy. Activation of the RAS-RAF-MEK signaling axis protects against this atrophy through a MEK-dependent autophagy mechanism. BRAF also protects against neuronal atrophy induced by mitochondrial impairment.","method":"siRNA knockdown of DYNC1I1 in primary hippocampal neurons; rescue experiments with RAS-RAF-MEK pathway activators; autophagy readouts","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype (neuronal atrophy) linked to DYNC1I1 loss with pathway rescue experiments; single lab, multiple mechanistic readouts","pmids":["27510948"],"is_preprint":false},{"year":2022,"finding":"GPM6A downregulation (driven by the circCCNB1/miR-106b-5p ceRNA axis) leads to increased DYNC1I1 expression, which activates phosphorylation of the AKT/ERK signaling pathway to regulate the HCC cell cycle.","method":"ceRNA network construction; transfection of miRNA mimics/inhibitors; circRNA silencing/overexpression; xenograft tumor assays; western blot for AKT/ERK phosphorylation","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — DYNC1I1 acts downstream of GPM6A and upstream of AKT/ERK, but the direct mechanistic link between DYNC1I1 and AKT/ERK phosphorylation is not biochemically resolved; single lab, no independent replication","pmids":["35002514"],"is_preprint":false},{"year":2023,"finding":"Dync1i1 knockout mice show impaired nociception (mechanical, thermal, and cold pain). This is associated with impaired activity of parvalbumin (PV) interneurons and reduced gamma oscillations in the primary somatosensory cortex. Optogenetic activation of PV neurons rescued pain sensation in Dync1i1-/- mice, and chemogenetic suppression of PV neurons in WT mice mimicked the phenotype.","method":"Dync1i1 knockout mouse model; in vivo electrophysiology; optogenetic activation of PV neurons; chemogenetic suppression of PV neurons; behavioral nociception assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined neuronal phenotype and causal pathway placement via bidirectional optogenetic/chemogenetic rescue and mimicry; single lab","pmids":["37257662"],"is_preprint":false},{"year":2025,"finding":"CLASP1 interacts with DYNC1I1 in mouse oocyte meiosis; DYNC1I1 functions as a downstream motor protein of CLASP1 involved in the orderly transport of PLK1 for spindle organization and cytokinesis during meiosis I.","method":"Co-immunoprecipitation/interaction assays; CLASP1 knockdown in mouse oocytes with spindle organization and cytokinesis phenotypic readouts; PLK1 localization analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein–protein interaction between CLASP1 and DYNC1I1 established, with functional placement of DYNC1I1 downstream of CLASP1 for PLK1 transport; single lab, interaction method not fully detailed in abstract","pmids":["40501366"],"is_preprint":false}],"current_model":"DYNC1I1 encodes a neuron-enriched intermediate chain of cytoplasmic dynein-1 that serves multiple mechanistic roles: its exons 15 and 17 act as tissue-specific cis-enhancers driving DLX5/6 expression in limb development; in neurons, DYNC1I1 is required for neuronal architecture maintenance and pain-related PV interneuron activity in the somatosensory cortex via RAS-RAF-MEK/autophagy-dependent protective pathways; in oocyte meiosis it interacts with CLASP1 as a downstream motor to transport PLK1 for spindle organization and cytokinesis; and in cancer contexts it drives proliferation and migration through NF-κB–IL-6/STAT and SP1–TNPO2 axes."},"narrative":{"mechanistic_narrative":"DYNC1I1 is a dynein-associated intermediate chain whose locus and protein contribute to both developmental gene regulation and neuronal and mitotic transport functions [PMID:24459211, PMID:25231166, PMID:40501366]. At the genomic level, exons 15 and 17 of DYNC1I1 act as tissue-specific cis-enhancers that drive expression of the adjacent DLX5/DLX6 genes during limb development; rearrangements that uncouple these exons from DLX5/6, or deletions removing the exons while leaving DLX5/6 intact, cause split-hand/split-foot malformation [PMID:24459211, PMID:25231166]. As a motor-pathway component, DYNC1I1 functions downstream of CLASP1 to transport PLK1 for spindle organization and cytokinesis during oocyte meiosis I [PMID:40501366]. In neurons, loss of DYNC1I1 causes neuronal atrophy that is counteracted by RAS-RAF-MEK signaling through a MEK-dependent autophagy mechanism [PMID:27510948], and Dync1i1 knockout impairs nociception by reducing parvalbumin interneuron activity and gamma oscillations in the primary somatosensory cortex, a deficit reversible by optogenetic activation of those interneurons [PMID:37257662]. In cancer, DYNC1I1 promotes proliferation and migration through NF-κB-driven IL-6/STAT signaling [PMID:31249807] and through an SP1-P300-TNPO2 transcriptional axis [PMID:31605449].","teleology":[{"year":2014,"claim":"Established that DYNC1I1 contributes to limb development not through its protein but through exonic cis-enhancers that regulate neighboring DLX5/6, explaining a Mendelian limb malformation.","evidence":"WGS breakpoint mapping and CNV/exome analysis of split-hand/split-foot malformation families","pmids":["24459211","25231166"],"confidence":"High","gaps":["Does not address the function of the DYNC1I1 protein product itself","Mechanism of how the exonic enhancers physically contact DLX5/6 not resolved"]},{"year":2016,"claim":"Showed that DYNC1I1 is required to maintain neuronal architecture, placing its loss upstream of a protective RAS-RAF-MEK/autophagy axis.","evidence":"siRNA knockdown in primary hippocampal neurons with pathway-activator rescue and autophagy readouts","pmids":["27510948"],"confidence":"Medium","gaps":["Molecular link between DYNC1I1 loss and atrophy not biochemically defined","Single lab, no in vivo confirmation","How MEK-dependent autophagy compensates for DYNC1I1 loss unresolved"]},{"year":2019,"claim":"Defined two cancer-promoting effector arms of DYNC1I1, connecting it to NF-κB/IL-6/STAT and to SP1-P300-TNPO2 transcriptional programs in gastric cancer.","evidence":"Knockdown/overexpression with proliferation/migration assays, xenografts, NF-κB translocation assays, expression chip and promoter acetylation assays","pmids":["31249807","31605449"],"confidence":"Medium","gaps":["Whether DYNC1I1 acts via its motor function or independently in these pathways is unclear","Direct molecular trigger of NF-κB translocation by DYNC1I1 not shown","Single lab for each axis"]},{"year":2023,"claim":"Demonstrated a circuit-level role for DYNC1I1 in pain processing, linking it to parvalbumin interneuron activity and cortical gamma oscillations.","evidence":"Dync1i1 knockout mice with in vivo electrophysiology, optogenetic/chemogenetic manipulation, and nociception behavior","pmids":["37257662"],"confidence":"Medium","gaps":["Cell-autonomous mechanism within PV interneurons not defined","How dynein intermediate chain loss alters interneuron activity unresolved","Single lab"]},{"year":2025,"claim":"Placed DYNC1I1 as a downstream motor of CLASP1 for PLK1 transport, integrating it into the meiotic spindle and cytokinesis machinery.","evidence":"Co-immunoprecipitation and CLASP1 knockdown in mouse oocytes with spindle/cytokinesis and PLK1 localization readouts","pmids":["40501366"],"confidence":"Medium","gaps":["Interaction method not fully detailed and reciprocal validation not described","Direct cargo-binding interface for PLK1 not mapped","Single lab"]},{"year":null,"claim":"How the diverse roles of DYNC1I1 — enhancer activity, neuronal maintenance, meiotic transport, and cancer signaling — relate to its canonical dynein intermediate-chain function remains unintegrated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of DYNC1I1 within dynein-1 in these contexts","Whether cancer and neuronal phenotypes depend on motor activity untested","No unifying mechanism linking the genomic enhancer role to the protein's transport role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[6]}],"localization":[],"pathway":[],"complexes":[],"partners":["CLASP1","PLK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14576","full_name":"Cytoplasmic dynein 1 intermediate chain 1","aliases":["Cytoplasmic dynein intermediate chain 1","Dynein intermediate chain 1, cytosolic","DH IC-1"],"length_aa":645,"mass_kda":73.0,"function":"Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. The intermediate chains mediate the binding of dynein to dynactin via its 150 kDa component (p150-glued) DCTN1. May play a role in mediating the interaction of cytoplasmic dynein with membranous organelles and kinetochores","subcellular_location":"Cytoplasm; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/O14576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DYNC1I1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DYNC1I1","total_profiled":1310},"omim":[{"mim_id":"615503","title":"SHORT-RIB THORACIC DYSPLASIA 8 WITH OR WITHOUT POLYDACTYLY; SRTD8","url":"https://www.omim.org/entry/615503"},{"mim_id":"615462","title":"DYNEIN, CYTOPLASMIC 2, INTERMEDIATE CHAIN 1; DYNC2I1","url":"https://www.omim.org/entry/615462"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"610296","title":"NUDC DOMAIN-CONTAINING PROTEIN 3; NUDCD3","url":"https://www.omim.org/entry/610296"},{"mim_id":"604350","title":"RAS-ASSOCIATED PROTEIN RAB3D; RAB3D","url":"https://www.omim.org/entry/604350"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":61.4}],"url":"https://www.proteinatlas.org/search/DYNC1I1"},"hgnc":{"alias_symbol":["DNCIC1"],"prev_symbol":["DNCI1"]},"alphafold":{"accession":"O14576","domains":[{"cath_id":"2.130.10.10","chopping":"272-425","consensus_level":"medium","plddt":85.4126,"start":272,"end":425},{"cath_id":"2.130.10.10","chopping":"433-645","consensus_level":"medium","plddt":83.7896,"start":433,"end":645}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14576","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14576-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DYNC1I1","jax_strain_url":"https://www.jax.org/strain/search?query=DYNC1I1"},"sequence":{"accession":"O14576","fasta_url":"https://rest.uniprot.org/uniprotkb/O14576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14576"}},"corpus_meta":[{"pmid":"24459211","id":"PMC_24459211","title":"Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans.","date":"2014","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24459211","citation_count":35,"is_preprint":false},{"pmid":"25231166","id":"PMC_25231166","title":"Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families.","date":"2014","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25231166","citation_count":35,"is_preprint":false},{"pmid":"35002514","id":"PMC_35002514","title":"CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35002514","citation_count":29,"is_preprint":false},{"pmid":"31249807","id":"PMC_31249807","title":"DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31249807","citation_count":29,"is_preprint":false},{"pmid":"26075025","id":"PMC_26075025","title":"7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance.","date":"2015","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26075025","citation_count":18,"is_preprint":false},{"pmid":"27510948","id":"PMC_27510948","title":"Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling.","date":"2016","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/27510948","citation_count":16,"is_preprint":false},{"pmid":"31605449","id":"PMC_31605449","title":"TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31605449","citation_count":12,"is_preprint":false},{"pmid":"37257662","id":"PMC_37257662","title":"Pain sensitivity related to gamma oscillation of parvalbumin interneuron in primary somatosensory cortex in Dync1i1-/- mice.","date":"2023","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37257662","citation_count":9,"is_preprint":false},{"pmid":"27291887","id":"PMC_27291887","title":"A novel description of a syndrome consisting of 7q21.3 deletion including DYNC1I1 with preserved DLX5/6 without ectrodactyly: a case report.","date":"2016","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/27291887","citation_count":9,"is_preprint":false},{"pmid":"35414776","id":"PMC_35414776","title":"Erratum: CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway: Erratum.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35414776","citation_count":3,"is_preprint":false},{"pmid":"40501366","id":"PMC_40501366","title":"CLASP1 regulates DYNC1I1 for PLK1-mediated spindle organization and cytokinesis in oocyte meiosis.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/40501366","citation_count":2,"is_preprint":false},{"pmid":"35280738","id":"PMC_35280738","title":"Corrigendum: DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35280738","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8074,"output_tokens":2030,"usd":0.027336,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8979,"output_tokens":2052,"usd":0.048098,"stage2_stop_reason":"end_turn"},"total_usd":0.075434,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Exons 15 and 17 of DYNC1I1 function as tissue-specific limb enhancers (exonic enhancers) that cis-regulate the expression of the adjacent genes DLX5 and DLX6 during limb development. Chromosomal rearrangements that separate these DYNC1I1 exons from DLX5/6, or deletions encompassing only these exons while leaving DLX5/6 disomic, cause split-hand/split-foot malformation in humans.\",\n      \"method\": \"Whole genome sequencing of chromosomal rearrangement breakpoints; copy number analysis via exome sequencing identifying 106 kb deletion removing DYNC1I1 exons 15/17 while DLX5/6 remain intact\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across two independent families in one paper (PMID:24459211) and confirmed in additional families by array CGH in a separate cohort study (PMID:25231166); orthogonal methods (WGS breakpoint mapping + CNV analysis) converge on the same mechanistic conclusion\",\n      \"pmids\": [\"24459211\", \"25231166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DYNC1I1 promotes gastric cancer cell proliferation and migration by upregulating IL-6 expression through increasing NF-κB nuclear translocation, thereby activating the IL-6/STAT signaling pathway.\",\n      \"method\": \"In vitro knockdown/overexpression assays (proliferation, migration), in vivo xenograft assays, NF-κB nuclear translocation assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype and pathway placement (NF-κB nuclear translocation measured), but single lab with no independent replication\",\n      \"pmids\": [\"31249807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DYNC1I1 upregulates TNPO2 expression by upregulating the transcription factor SP1, which then recruits and binds to P300-acetylated histone regions at the TNPO2 promoter to drive TNPO2 transcription. TNPO2 in turn promotes gastric cancer cell proliferation and inhibits apoptosis, potentially via P21.\",\n      \"method\": \"Expression profile chip identifying TNPO2 as downstream target; mechanistic follow-up with transcription factor binding and promoter acetylation assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement established via expression chip and promoter assays in single lab; SP1/P300 mechanism described but relies on a single lab without independent replication\",\n      \"pmids\": [\"31605449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DYNC1I1 deficiency in primary hippocampal neurons causes neuronal atrophy. Activation of the RAS-RAF-MEK signaling axis protects against this atrophy through a MEK-dependent autophagy mechanism. BRAF also protects against neuronal atrophy induced by mitochondrial impairment.\",\n      \"method\": \"siRNA knockdown of DYNC1I1 in primary hippocampal neurons; rescue experiments with RAS-RAF-MEK pathway activators; autophagy readouts\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype (neuronal atrophy) linked to DYNC1I1 loss with pathway rescue experiments; single lab, multiple mechanistic readouts\",\n      \"pmids\": [\"27510948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPM6A downregulation (driven by the circCCNB1/miR-106b-5p ceRNA axis) leads to increased DYNC1I1 expression, which activates phosphorylation of the AKT/ERK signaling pathway to regulate the HCC cell cycle.\",\n      \"method\": \"ceRNA network construction; transfection of miRNA mimics/inhibitors; circRNA silencing/overexpression; xenograft tumor assays; western blot for AKT/ERK phosphorylation\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — DYNC1I1 acts downstream of GPM6A and upstream of AKT/ERK, but the direct mechanistic link between DYNC1I1 and AKT/ERK phosphorylation is not biochemically resolved; single lab, no independent replication\",\n      \"pmids\": [\"35002514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dync1i1 knockout mice show impaired nociception (mechanical, thermal, and cold pain). This is associated with impaired activity of parvalbumin (PV) interneurons and reduced gamma oscillations in the primary somatosensory cortex. Optogenetic activation of PV neurons rescued pain sensation in Dync1i1-/- mice, and chemogenetic suppression of PV neurons in WT mice mimicked the phenotype.\",\n      \"method\": \"Dync1i1 knockout mouse model; in vivo electrophysiology; optogenetic activation of PV neurons; chemogenetic suppression of PV neurons; behavioral nociception assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined neuronal phenotype and causal pathway placement via bidirectional optogenetic/chemogenetic rescue and mimicry; single lab\",\n      \"pmids\": [\"37257662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLASP1 interacts with DYNC1I1 in mouse oocyte meiosis; DYNC1I1 functions as a downstream motor protein of CLASP1 involved in the orderly transport of PLK1 for spindle organization and cytokinesis during meiosis I.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays; CLASP1 knockdown in mouse oocytes with spindle organization and cytokinesis phenotypic readouts; PLK1 localization analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein–protein interaction between CLASP1 and DYNC1I1 established, with functional placement of DYNC1I1 downstream of CLASP1 for PLK1 transport; single lab, interaction method not fully detailed in abstract\",\n      \"pmids\": [\"40501366\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DYNC1I1 encodes a neuron-enriched intermediate chain of cytoplasmic dynein-1 that serves multiple mechanistic roles: its exons 15 and 17 act as tissue-specific cis-enhancers driving DLX5/6 expression in limb development; in neurons, DYNC1I1 is required for neuronal architecture maintenance and pain-related PV interneuron activity in the somatosensory cortex via RAS-RAF-MEK/autophagy-dependent protective pathways; in oocyte meiosis it interacts with CLASP1 as a downstream motor to transport PLK1 for spindle organization and cytokinesis; and in cancer contexts it drives proliferation and migration through NF-κB–IL-6/STAT and SP1–TNPO2 axes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DYNC1I1 is a dynein-associated intermediate chain whose locus and protein contribute to both developmental gene regulation and neuronal and mitotic transport functions [#0, #6]. At the genomic level, exons 15 and 17 of DYNC1I1 act as tissue-specific cis-enhancers that drive expression of the adjacent DLX5/DLX6 genes during limb development; rearrangements that uncouple these exons from DLX5/6, or deletions removing the exons while leaving DLX5/6 intact, cause split-hand/split-foot malformation [#0]. As a motor-pathway component, DYNC1I1 functions downstream of CLASP1 to transport PLK1 for spindle organization and cytokinesis during oocyte meiosis I [#6]. In neurons, loss of DYNC1I1 causes neuronal atrophy that is counteracted by RAS-RAF-MEK signaling through a MEK-dependent autophagy mechanism [#3], and Dync1i1 knockout impairs nociception by reducing parvalbumin interneuron activity and gamma oscillations in the primary somatosensory cortex, a deficit reversible by optogenetic activation of those interneurons [#5]. In cancer, DYNC1I1 promotes proliferation and migration through NF-\\u03baB-driven IL-6/STAT signaling [#1] and through an SP1-P300-TNPO2 transcriptional axis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that DYNC1I1 contributes to limb development not through its protein but through exonic cis-enhancers that regulate neighboring DLX5/6, explaining a Mendelian limb malformation.\",\n      \"evidence\": \"WGS breakpoint mapping and CNV/exome analysis of split-hand/split-foot malformation families\",\n      \"pmids\": [\"24459211\", \"25231166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address the function of the DYNC1I1 protein product itself\", \"Mechanism of how the exonic enhancers physically contact DLX5/6 not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that DYNC1I1 is required to maintain neuronal architecture, placing its loss upstream of a protective RAS-RAF-MEK/autophagy axis.\",\n      \"evidence\": \"siRNA knockdown in primary hippocampal neurons with pathway-activator rescue and autophagy readouts\",\n      \"pmids\": [\"27510948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between DYNC1I1 loss and atrophy not biochemically defined\", \"Single lab, no in vivo confirmation\", \"How MEK-dependent autophagy compensates for DYNC1I1 loss unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined two cancer-promoting effector arms of DYNC1I1, connecting it to NF-\\u03baB/IL-6/STAT and to SP1-P300-TNPO2 transcriptional programs in gastric cancer.\",\n      \"evidence\": \"Knockdown/overexpression with proliferation/migration assays, xenografts, NF-\\u03baB translocation assays, expression chip and promoter acetylation assays\",\n      \"pmids\": [\"31249807\", \"31605449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DYNC1I1 acts via its motor function or independently in these pathways is unclear\", \"Direct molecular trigger of NF-\\u03baB translocation by DYNC1I1 not shown\", \"Single lab for each axis\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a circuit-level role for DYNC1I1 in pain processing, linking it to parvalbumin interneuron activity and cortical gamma oscillations.\",\n      \"evidence\": \"Dync1i1 knockout mice with in vivo electrophysiology, optogenetic/chemogenetic manipulation, and nociception behavior\",\n      \"pmids\": [\"37257662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous mechanism within PV interneurons not defined\", \"How dynein intermediate chain loss alters interneuron activity unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed DYNC1I1 as a downstream motor of CLASP1 for PLK1 transport, integrating it into the meiotic spindle and cytokinesis machinery.\",\n      \"evidence\": \"Co-immunoprecipitation and CLASP1 knockdown in mouse oocytes with spindle/cytokinesis and PLK1 localization readouts\",\n      \"pmids\": [\"40501366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction method not fully detailed and reciprocal validation not described\", \"Direct cargo-binding interface for PLK1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse roles of DYNC1I1 — enhancer activity, neuronal maintenance, meiotic transport, and cancer signaling — relate to its canonical dynein intermediate-chain function remains unintegrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of DYNC1I1 within dynein-1 in these contexts\", \"Whether cancer and neuronal phenotypes depend on motor activity untested\", \"No unifying mechanism linking the genomic enhancer role to the protein's transport role\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CLASP1\", \"PLK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}