Affinage

DYNC1I1

Cytoplasmic dynein 1 intermediate chain 1 · UniProt O14576

Length
645 aa
Mass
73.0 kDa
Annotated
2026-06-09
12 papers in source corpus 8 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2014 High

    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

    PMID:24459211 PMID:25231166

    Open questions at the time
    • Does not address the function of the DYNC1I1 protein product itself
    • Mechanism of how the exonic enhancers physically contact DLX5/6 not resolved
  2. 2016 Medium

    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

    PMID:27510948

    Open questions at the time
    • 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
  3. 2019 Medium

    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

    PMID:31249807 PMID:31605449

    Open questions at the time
    • 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
  4. 2023 Medium

    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

    PMID:37257662

    Open questions at the time
    • Cell-autonomous mechanism within PV interneurons not defined
    • How dynein intermediate chain loss alters interneuron activity unresolved
    • Single lab
  5. 2025 Medium

    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

    PMID:40501366

    Open questions at the time
    • Interaction method not fully detailed and reciprocal validation not described
    • Direct cargo-binding interface for PLK1 not mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 1
Partners
CLASP1PLK1

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. 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 of medical genetics High 24459211 25231166
2019 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. In vitro knockdown/overexpression assays (proliferation, migration), in vivo xenograft assays, NF-κB nuclear translocation assays Frontiers in oncology Medium 31249807
2019 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. Expression profile chip identifying TNPO2 as downstream target; mechanistic follow-up with transcription factor binding and promoter acetylation assays Cancer medicine Medium 31605449
2016 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. siRNA knockdown of DYNC1I1 in primary hippocampal neurons; rescue experiments with RAS-RAF-MEK pathway activators; autophagy readouts Protein & cell Medium 27510948
2022 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. ceRNA network construction; transfection of miRNA mimics/inhibitors; circRNA silencing/overexpression; xenograft tumor assays; western blot for AKT/ERK phosphorylation International journal of biological sciences Low 35002514
2023 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. Dync1i1 knockout mouse model; in vivo electrophysiology; optogenetic activation of PV neurons; chemogenetic suppression of PV neurons; behavioral nociception assays Neurobiology of disease Medium 37257662
2025 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. Co-immunoprecipitation/interaction assays; CLASP1 knockdown in mouse oocytes with spindle organization and cytokinesis phenotypic readouts; PLK1 localization analysis Journal of cell science Medium 40501366

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 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. Journal of medical genetics 35 24459211
2014 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. Orphanet journal of rare diseases 35 25231166
2022 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. International journal of biological sciences 29 35002514
2019 DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression. Frontiers in oncology 29 31249807
2015 7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance. Molecular cytogenetics 18 26075025
2016 Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling. Protein & cell 16 27510948
2019 TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis. Cancer medicine 12 31605449
2023 Pain sensitivity related to gamma oscillation of parvalbumin interneuron in primary somatosensory cortex in Dync1i1-/- mice. Neurobiology of disease 9 37257662
2016 A novel description of a syndrome consisting of 7q21.3 deletion including DYNC1I1 with preserved DLX5/6 without ectrodactyly: a case report. Journal of medical case reports 9 27291887
2022 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. International journal of biological sciences 3 35414776
2025 CLASP1 regulates DYNC1I1 for PLK1-mediated spindle organization and cytokinesis in oocyte meiosis. Journal of cell science 2 40501366
2022 Corrigendum: DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression. Frontiers in oncology 1 35280738

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