{"gene":"NDE1","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2004,"finding":"Nde1 (mNudE) is essential for centrosome duplication and mitotic spindle assembly in cortical progenitors; Nde1 ablation in mouse causes defects in mitotic progression, mitotic orientation, and mitotic chromosome localization, resulting in reduced progenitor cell division and altered neuronal cell fates leading to microcephaly.","method":"Mouse knockout (Nde1-null), BrdU birthdating, in vitro centrosome duplication and spindle assembly assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype replicated in vivo and validated by in vitro assays","pmids":["15473967"],"is_preprint":false},{"year":2010,"finding":"NudE (NDE1) stably recruits LIS1 to the dynein holoenzyme, where LIS1 interacts with the motor domain during the prepowerstroke state. NudE alone abrogates dynein force production, whereas LIS1 alone or with NudE induces a persistent-force dynein state that enhances ensemble function of multiple dyneins under high-load conditions.","method":"Single-molecule optical trapping assays, biochemical reconstitution with purified proteins, force measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with force measurements, mechanistic dissection of dynein states","pmids":["20403325"],"is_preprint":false},{"year":2011,"finding":"Nde1 localizes to the mother centriole and functions as a negative regulator of ciliary length. Nde1 is expressed at high levels in mitosis and low levels in quiescence; cells depleted of Nde1 have longer cilia and a delay in cell cycle re-entry that correlates with ciliary length.","method":"Nde1 knockdown (siRNA/shRNA), immunofluorescence localization, zebrafish morpholino knockdown, cell cycle re-entry assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, live imaging, in vivo zebrafish), strong phenotypic-mechanistic link","pmids":["21394081"],"is_preprint":false},{"year":2011,"finding":"Human NDE1 C-terminal domain is required for interaction with cytoplasmic dynein and for cell-cycle-dependent phosphorylation by Cdk1 at T246. Patient frameshift mutations truncating the C-terminus render NDE1 proteins unstable, unable to bind dynein, and unable to localize to the centrosome. CDK1 phosphorylation at T246 is required for cell-cycle progression from G2 to M phase.","method":"Patient cell lines, transfection of tagged NDE1 constructs, co-immunoprecipitation, immunofluorescence, CDK1 phosphorylation assays, cell cycle analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient cells, functional rescue experiments, kinase assays","pmids":["21529751"],"is_preprint":false},{"year":2011,"finding":"NDE1 mutation (c.684_685del) results in a protein unable to localize to the centrosome. NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis; NDE1 deficiency causes severe failure of neurogenesis and deficiency in cortical lamination.","method":"Patient-derived cell lines, immunofluorescence, transfection of tagged NDE1 constructs, human and mouse embryonic brain staining","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — patient cells with multiple orthogonal localization and functional assays","pmids":["21529752"],"is_preprint":false},{"year":2007,"finding":"Cenp-F interacts with both Ndel1 and Nde1 and recruits them (along with Lis1) to kinetochores. Nde1 (but not Ndel1) is required for kinetochore localization of Dynein. Suppression of Nde1 inhibits metaphase chromosome alignment and activates the spindle checkpoint.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, spindle checkpoint assays","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA with defined cellular phenotypes, clear functional distinction between NDE1 and NDEL1","pmids":["17600710"],"is_preprint":false},{"year":2007,"finding":"NudE and NudEL each localize to mitotic kinetochores before dynein, dynactin, ZW10, and LIS1. Inhibition of NudE/NudEL causes metaphase arrest with misoriented chromosomes and defective microtubule attachment. Dynein (through its intermediate and light chains, not motor domain) interacts with NudE, and both dynein and dynactin are displaced from kinetochores by anti-NudE/NudEL antibody injection.","method":"Anti-NudE/NudEL antibody microinjection, immunofluorescence, co-immunoprecipitation, time-lapse imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — antibody injection functional assay, Co-IP mapping of interaction domain, replicated by two independent groups","pmids":["17682047"],"is_preprint":false},{"year":2010,"finding":"NDE1 and NDEL1 are membrane-associated and their depletion leads to complete loss of dynein from membranes and dispersal of Golgi and endocytic compartments. NDE1 and NDEL1 act upstream of LIS1 in dynein recruitment/activation on membranes; exogenous NDE1 or NDEL1 can rescue LIS1 depletion effects on Golgi organization.","method":"siRNA knockdown, immunofluorescence, subcellular fractionation, organelle position assays, epistasis rescue experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via rescue experiments, fractionation showing membrane association, multiple organelle readouts","pmids":["20048338"],"is_preprint":false},{"year":2003,"finding":"Nudel (NDEL1, the NDE1 paralog) is phosphorylated in M phase by Cdc2 and Erk1/2. Phosphorylation regulates cell-cycle-dependent distribution of Nudel and increases its binding to Lis1. A Nudel mutant incapable of binding Lis1 impairs poleward movement of dynein and dynein-mediated transport of kinetochore proteins to spindle poles. NudE (NDE1) is functionally related to Nudel in this context.","method":"Phospho-specific mutants, co-immunoprecipitation, live-cell imaging, in vitro kinase assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay and functional mutant analysis; primary findings on NDEL1 but NDE1 comparative data included","pmids":["12556484"],"is_preprint":false},{"year":2011,"finding":"NudE (NDE1) and dynactin bind to a common region within the dynein intermediate chain (IC) and compete for this site. NudE binds dynein through its LC8 and IC subunits. NudE and dynactin form mutually exclusive complexes with dynein, preventing dual regulation of individual dynein molecules.","method":"In vitro binding assays, co-immunoprecipitation, competitive binding experiments, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with competitive binding and mutagenesis demonstrating mutually exclusive interactions","pmids":["21911489"],"is_preprint":false},{"year":2008,"finding":"LIS1 and Nde1 collaboratively regulate the fate of radial glial progenitors. Mice with allelic series of Lis1 and Nde1 double mutations show dose-dependent cortical size reduction and delamination. Lis1-Nde1 deficiency alters metaphase progenitor morphology, reducing apical attachment and lateral contacts, which disrupts asymmetric cell division and causes premature neuronal differentiation.","method":"Double-mutant mouse genetics (epistasis), immunohistochemistry, BrdU/EdU birthdating, confocal imaging","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with allelic series, strong dose-dependent phenotype","pmids":["18469343"],"is_preprint":false},{"year":2006,"finding":"Nde1 forms a complex with the centrosomal protein Su48. Nde1 is phosphorylated by Cdc2 in vivo at six putative sites; mutation of these sites diminishes phosphorylation, affects stability of Su48-Nde1 interactions, and affects centrosomal localization of Nde1. Ablation of Nde1 by siRNA causes mitotic delay and cell death.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro Cdc2 kinase assay, phospho-site mutagenesis, siRNA knockdown, immunofluorescence","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — kinase assay with mutagenesis, Y2H confirmed by Co-IP, functional siRNA phenotype","pmids":["16682949"],"is_preprint":false},{"year":2006,"finding":"Nde1 associates with p78/MCRS1 (a protein with a forkhead-associated domain) at the centrosome. The association between p78 and Nde1 is regulated by phosphorylation on Nde1. Abrogation of p78 by siRNA causes cell death and mitotic delay.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP confirmed interaction, functional siRNA; single lab","pmids":["16547491"],"is_preprint":false},{"year":2011,"finding":"DISC1, NDE1, NDEL1, LIS1, dynein, PDE4B, and PDE4D associate together in a centrosomal complex in mammalian cells. NDE1 is phosphorylated by PKA at a novel site. This DISC1-PDE4 modulated complex is present at the centrosome, and NDE1/NDEL1/LIS1 complex is proposed to localize at synapses.","method":"Co-immunoprecipitation, immunofluorescence, phospho-site mapping, synaptic localization in cultured neurons","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and localization data; single lab, multiple readouts","pmids":["18983980"],"is_preprint":false},{"year":2011,"finding":"DISC1 and PDE4 modulate NDE1 phosphorylation by PKA at threonine-131 (T131). Phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions. T131-phosphorylated NDE1 is enriched at the centrosome during mitosis. Mutation mimicking PKA phosphorylation at T131 inhibits neurite outgrowth.","method":"Homology modeling, co-immunoprecipitation, phospho-specific antibody, neurite outgrowth assay, immunofluorescence","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — phospho-site mutagenesis validated by Co-IP and functional assay; single lab","pmids":["21677187"],"is_preprint":false},{"year":2015,"finding":"NDE1 protein levels are regulated by the E3 ubiquitin ligase FBW7 in a CDK5-dependent manner upon G1 entry. CDK5 primes NDE1 for FBW7-mediated recognition and destruction. Cells depleted of FBW7 or CDK5 show elevated NDE1 levels and reduced ciliary length, which is corrected by simultaneous NDE1 depletion, establishing a CDK5-FBW7-NDE1 pathway controlling ciliary length.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitylation assays, cell cycle synchronization, cilia length measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — ubiquitylation assay identifying E3 ligase, CDK5 priming, epistasis rescue; multiple orthogonal methods","pmids":["26206584"],"is_preprint":false},{"year":2016,"finding":"NDE1 RNAi in embryonic rat brains causes cell cycle arrest of neural progenitors at three distinct stages: during apical interkinetic nuclear migration, at G2-to-M transition, and in regulation of primary cilia at G1-to-S transition. NDEL1 RNAi does not recapitulate these mitotic arrest phenotypes, revealing a unique NDE1 role at G2-to-M, though NDEL1 overexpression can compensate for NDE1 at other stages.","method":"In utero electroporation of shRNA, immunofluorescence, time-lapse imaging, cell cycle stage markers","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in utero electroporation with defined stage-specific phenotypes, NDE1 vs NDEL1 dissection","pmids":["27553190"],"is_preprint":false},{"year":2014,"finding":"NDE1 has a nuclear pool that interacts with cohesin and its associated chromatin remodeler. Loss of Nde1 causes DNA double-strand breaks during mid-late S phase at heterochromatin domains, activating p53-dependent apoptosis. This reveals a role for NDE1 in safeguarding heterochromatin replication during S phase.","method":"Co-immunoprecipitation (Nde1-cohesin), immunofluorescence (DNA damage markers), FACS cell cycle analysis, Nde1 mutant neural progenitors","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifying novel nuclear interaction, DSB phenotype in mutant cells; single lab, relatively new finding","pmids":["25245017"],"is_preprint":false},{"year":2012,"finding":"Full-length NDE1 forms dimers, tetramers, and chain-like end-to-end polymers in solution. The C-terminal domain adopts a bent-back structure allowing it to interact with the N-terminal coiled-coil domain. NDE1 and NDEL1 can form mixed complexes. The C-terminal region (disrupted by disease mutations) is required for interaction with dynein and DISC1.","method":"Negative stain electron microscopy, chemical cross-linking/mass spectrometry, isotope labeling, homology modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct structural characterization with multiple orthogonal biophysical methods","pmids":["22843697"],"is_preprint":false},{"year":2012,"finding":"The NDE1 N-terminal domain (forming a dimeric coiled-coil) interacts with the N-terminal domain of dynein intermediate chain (IC). NudE binds region 1 of the bi-segmental IC binding footprint used by p150(Glued)/dynactin, and when all three proteins are in solution, IC preferentially binds p150(Glued) despite NudE having higher affinity for the common segment alone.","method":"Isothermal titration calorimetry, NMR spectroscopy, competition binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — ITC and NMR with mutagenesis-level precision for interaction mapping","pmids":["22669947"],"is_preprint":false},{"year":2013,"finding":"The Nde1-Lis1 complex directly interacts with Brap, a MAPK signaling threshold modulator. Nde1-Lis1 deficiency causes spatially dependent hyperactivation of MAPK via altered Ksr scaffold; epistasis analyses support synergistic Brap and Lis1 functions in regulating cell fate decisions based on geographic proximity to midline signaling centers.","method":"Co-immunoprecipitation, double-mutant epistasis in mouse, immunofluorescence of MAPK pathway components","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and in vivo epistasis; single lab but multiple approaches","pmids":["23673330"],"is_preprint":false},{"year":2011,"finding":"Nde1 directly interacts with utrophin/dystrophin, allowing assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of radial glial cells (RGCs). Lis1-Nde1 mutations destabilize the dystrophin glycoprotein complex (DGC) and deform RGCs, disrupting basal lamina, RGC self-renewal, and neuronal migration.","method":"Co-immunoprecipitation, immunofluorescence, mouse genetics (Lis1-Nde1 mutants), genetic interaction with dystroglycan","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifying novel interaction, mouse genetics with epistasis; single lab","pmids":["22028625"],"is_preprint":false},{"year":2016,"finding":"NDE1 and dynactin form mutually exclusive complexes with dynein and exhibit non-overlapping distributions in T cells. NDE1/dynein complex mediates MTOC translocation to the immunological synapse, while dynactin/dynein complex mediates lytic granule transport. Dominant-negative NDE1 or NDE1 knockdown inhibits MTOC translocation and CTL-mediated killing.","method":"Dominant-negative NDE1 expression, siRNA knockdown in Jurkat and primary CTLs, immunofluorescence, killing assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional dissection of NDE1 vs dynactin roles with KD and DN constructs; single lab","pmids":["27534551"],"is_preprint":false},{"year":2017,"finding":"The high-resolution crystal structure of DISC1 C-terminal tail in complex with the Ndel1 binding domain was solved. DISC1 regulates Ndel1/Nde1 kinetochore attachment (but not centrosome localization) during mitosis. Disrupting DISC1/Ndel1 complex formation prolongs mitotic length and causes cell-cycle deficits in human cells, mouse embryonic cortex, and human forebrain organoids.","method":"X-ray crystallography, co-immunoprecipitation, DISC1 mutant overexpression, in utero electroporation, cerebral organoids from patient iPSCs","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with multiple functional assays across model systems","pmids":["29103808"],"is_preprint":false},{"year":2018,"finding":"CDK1 phosphorylates Nde1 in a cell cycle-dependent manner; phospho-Nde1 associates specifically with late G2-M nuclear envelope and prophase-to-anaphase kinetochores, mirroring CENP-F localization. Phosphomutant-Nde1 shows weaker CENP-F binding in vitro, establishing CENP-F as the first characterized Nde1 cargo protein. Expression of a dynein-binding-deficient Nde1 mutant reduces kinetochore dynein by half.","method":"NDE1 RNAi, phospho-specific antibody, phosphomimetic/phosphomutant cDNAs, in vitro binding assays, kinetochore dynein quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding assays with phosphomutants, phospho-specific antibody, functional RNAi phenotypes","pmids":["29930206"],"is_preprint":false}],"current_model":"NDE1 is a centrosomal scaffold protein that recruits LIS1 to cytoplasmic dynein to induce a persistent force-producing motor state, coordinates dynein localization to kinetochores (via CENP-F) and membranes in a CDK1/CDK5/PKA phosphorylation-dependent manner, negatively regulates primary cilia length through a CDK5-FBW7 ubiquitin-mediated degradation pathway, and is essential for neural progenitor cell-cycle progression (at IKN migration, G2-M, and G1-S transitions) and heterochromatin replication during S phase, with its C-terminal domain mediating interactions with dynein, LIS1, DISC1, and CENP-F that are disrupted by disease-causing truncation mutations."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that phosphorylation of the NDE1 paralog NDEL1 by Cdc2 and Erk1/2 regulates its binding to LIS1 and dynein-dependent kinetochore transport framed the paradigm that cell-cycle kinases control the NDE1/NDEL1–LIS1–dynein axis.","evidence":"Phospho-site mutagenesis, Co-IP, and live-cell imaging in mammalian cells focused on NDEL1 with comparative NDE1 data","pmids":["12556484"],"confidence":"Medium","gaps":["Primary data are on NDEL1; NDE1-specific phosphoregulation not independently dissected","In vivo relevance of individual phospho-sites for NDE1 unresolved"]},{"year":2004,"claim":"Demonstration that Nde1 knockout in mice causes microcephaly through failed centrosome duplication, spindle assembly, and mitotic progression in cortical progenitors established NDE1 as essential for brain size determination.","evidence":"Nde1-null mouse, BrdU birthdating, in vitro centrosome duplication and spindle assays","pmids":["15473967"],"confidence":"High","gaps":["Molecular mechanism linking NDE1 to centrosome duplication not identified","Whether NDE1 acts solely through dynein in this context was not tested"]},{"year":2006,"claim":"Identification of NDE1 as a Cdc2 substrate at multiple sites and as an interactor of centrosomal Su48 and p78/MCRS1 defined NDE1 as a phospho-regulated centrosomal hub whose loss causes mitotic delay and cell death.","evidence":"Yeast two-hybrid, Co-IP, in vitro Cdc2 kinase assay, phospho-site mutagenesis, siRNA knockdown","pmids":["16682949","16547491"],"confidence":"High","gaps":["Functional significance of individual Cdc2 phospho-sites on NDE1 not fully resolved","Whether Su48 and p78 interactions are direct or bridged through a common complex unclear"]},{"year":2007,"claim":"Showing that NDE1 (but not NDEL1) is specifically required for dynein recruitment to kinetochores via CENP-F, and that NDE1/NDEL1 arrive at kinetochores before dynein, established NDE1 as a kinetochore-targeting adaptor for the dynein motor.","evidence":"Co-IP, siRNA knockdown, antibody microinjection, immunofluorescence timing, spindle checkpoint assays","pmids":["17600710","17682047"],"confidence":"High","gaps":["Direct NDE1–CENP-F binding interface not mapped","Mechanism by which NDE1 recruits dynein to kinetochores (vs. stabilizes it there) unresolved"]},{"year":2008,"claim":"Double-mutant epistasis with LIS1 and NDE1 allelic series demonstrated dose-dependent collaboration in radial glial progenitor fate, linking the NDE1–LIS1 axis to asymmetric cell division and cortical lamination.","evidence":"Lis1/Nde1 compound mutant mice, BrdU/EdU birthdating, confocal imaging","pmids":["18469343"],"confidence":"High","gaps":["Whether the dose-dependent effect reflects a threshold of dynein activity or independent NDE1–LIS1 functions unknown"]},{"year":2010,"claim":"Single-molecule force measurements revealed that NDE1 recruits LIS1 to dynein and that together they induce a persistent-force motor state, providing the first biophysical mechanism for NDE1 function in high-load transport.","evidence":"Optical trapping with purified dynein, NDE1, and LIS1 proteins; biochemical reconstitution","pmids":["20403325"],"confidence":"High","gaps":["Whether the persistent-force state operates identically in vivo under cargo-load conditions untested","Role of NDE1 phosphorylation in modulating force production not examined"]},{"year":2010,"claim":"NDE1/NDEL1 were shown to be membrane-associated and required upstream of LIS1 for all dynein recruitment to Golgi and endosomal membranes, extending NDE1's adaptor role beyond kinetochores to organelle positioning.","evidence":"siRNA knockdown, subcellular fractionation, organelle dispersal assays, epistasis rescue of LIS1 depletion","pmids":["20048338"],"confidence":"High","gaps":["How NDE1 itself is targeted to membranes not identified","Relative contributions of NDE1 versus NDEL1 at membranes not separated"]},{"year":2011,"claim":"Multiple discoveries converged to define NDE1 as a cilia-length regulator, a dynein IC/dynactin-competing adaptor, a PKA/DISC1 signaling target, and the gene mutated in human microlissencephaly, revealing the breadth of NDE1 functions in cell cycle and brain development.","evidence":"Cilia length measurements after Nde1 KD and zebrafish morpholinos [PMID:21394081]; competitive binding assays showing NDE1 and dynactin are mutually exclusive on dynein IC [PMID:21911489]; patient cell lines with C-terminal truncations showing loss of dynein binding and centrosome localization [PMID:21529751, PMID:21529752]; PKA phosphorylation at T131 modulating NDE1–LIS1 interaction and neurite outgrowth [PMID:21677187]; NDE1–utrophin/DGC interaction in radial glia [PMID:22028625]","pmids":["21394081","21911489","21529751","21529752","21677187","22028625"],"confidence":"High","gaps":["How ciliary NDE1 function relates mechanistically to its centrosomal dynein role not resolved","Structural basis for mutual exclusivity of NDE1 and dynactin on dynein IC not determined","NDE1–utrophin interaction lacks independent replication"]},{"year":2012,"claim":"Structural studies showed NDE1 forms dimers, tetramers, and end-to-end polymers with a bent-back C-terminal domain, and that the NDE1 N-terminal coiled-coil binds dynein IC at a site overlapping with p150Glued, providing an atomic-level explanation for the competitive NDE1/dynactin relationship.","evidence":"Negative-stain EM, chemical cross-linking/mass spectrometry, ITC, NMR spectroscopy","pmids":["22843697","22669947"],"confidence":"High","gaps":["No high-resolution crystal structure of the full NDE1–dynein complex","Functional significance of NDE1 polymerization in vivo unknown"]},{"year":2013,"claim":"Discovery that the NDE1–LIS1 complex interacts with BRAP and modulates MAPK signaling thresholds revealed a signaling role for NDE1 beyond cytoskeletal motor regulation.","evidence":"Co-IP, double-mutant epistasis in mouse with MAPK pathway readouts","pmids":["23673330"],"confidence":"Medium","gaps":["Whether NDE1–BRAP interaction is direct or LIS1-mediated not resolved","Not independently replicated","Mechanism of MAPK modulation unclear"]},{"year":2014,"claim":"Identification of a nuclear NDE1 pool that interacts with cohesin and safeguards heterochromatin replication during S phase revealed a non-centrosomal function for NDE1 in genome integrity.","evidence":"Co-IP of Nde1 with cohesin, DNA damage markers in Nde1-mutant neural progenitors, FACS cell cycle analysis","pmids":["25245017"],"confidence":"Medium","gaps":["Whether NDE1 acts directly in replication fork protection or indirectly through cohesin loading is unknown","Nuclear NDE1 pool not independently replicated","Relationship to dynein-dependent functions unclear"]},{"year":2015,"claim":"Defining the CDK5–FBW7 ubiquitin-mediated degradation pathway for NDE1 at G1 entry established how cell-cycle-dependent NDE1 turnover controls cilia length and cell cycle re-entry.","evidence":"Ubiquitylation assays, CDK5 priming, epistasis rescue (FBW7 KD + NDE1 KD), cilia length measurements","pmids":["26206584"],"confidence":"High","gaps":["Whether other E3 ligases also target NDE1 not explored","How ciliary NDE1 is mechanistically linked to cilia disassembly or resorption not determined"]},{"year":2016,"claim":"In vivo dissection in embryonic rat brain revealed three distinct cell-cycle arrest points caused by NDE1 loss—interkinetic nuclear migration, G2-to-M, and G1-to-S (cilia)—that are not shared by NDEL1, and that NDE1/dynactin form functionally non-overlapping dynein complexes mediating MTOC translocation versus granule transport in T cells.","evidence":"In utero electroporation of shRNA with cell-cycle markers [PMID:27553190]; dominant-negative NDE1 and siRNA in CTLs with killing assays [PMID:27534551]","pmids":["27553190","27534551"],"confidence":"High","gaps":["How NDE1 specifically licenses G2-to-M transition molecularly (beyond CDK1 phosphorylation) unresolved","Whether NDE1's immune synapse role is relevant in vivo not tested"]},{"year":2017,"claim":"Crystal structure of the DISC1–NDEL1 complex and functional data showed DISC1 regulates NDE1/NDEL1 kinetochore attachment during mitosis; disruption of this complex prolongs mitosis and impairs cortical neurogenesis in organoids.","evidence":"X-ray crystallography, Co-IP, in utero electroporation, human cerebral organoids from patient iPSCs","pmids":["29103808"],"confidence":"High","gaps":["Structure solved for NDEL1; whether DISC1–NDE1 interface is identical not confirmed crystallographically","Contribution of DISC1–NDE1 versus DISC1–NDEL1 in human disease not separated"]},{"year":2018,"claim":"CDK1-phosphorylated NDE1 was shown to bind CENP-F directly, establishing CENP-F as the first characterized NDE1 cargo protein and explaining how phosphorylation gates NDE1 kinetochore localization and dynein recruitment.","evidence":"Phospho-specific antibody, phosphomimetic/phosphomutant in vitro binding assays, kinetochore dynein quantification after NDE1 RNAi","pmids":["29930206"],"confidence":"High","gaps":["Full phospho-code governing NDE1 localization across the cell cycle not mapped","Whether CENP-F–NDE1 interaction is sufficient or whether additional kinetochore factors are needed"]},{"year":null,"claim":"Key open questions include how NDE1's nuclear/cohesin role relates to its centrosomal dynein functions, what structural basis underlies NDE1 polymerization and its functional significance, and how context-specific kinase codes (CDK1, CDK5, PKA) are integrated to direct NDE1 to distinct subcellular destinations.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length NDE1 or NDE1–dynein complex","Nuclear versus centrosomal NDE1 pools not mechanistically connected","Integrated phospho-regulation model across CDK1, CDK5, and PKA lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,6,7,9,24]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,6,9,18,19]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2,3,4,11,13]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5,6,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3,5,6,11,16,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,10,16,23]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,20]}],"complexes":["NDE1–LIS1–dynein","DISC1–NDE1–NDEL1–PDE4"],"partners":["LIS1","DYNC1H1","CENP-F","DISC1","NDEL1","DCTN1","FBXW7","UTRN"],"other_free_text":[]},"mechanistic_narrative":"NDE1 is a centrosomal and kinetochore scaffold protein that coordinates cytoplasmic dynein localization, activation, and force production across multiple cellular contexts including mitotic spindle assembly, chromosome alignment, membrane trafficking, and primary cilia regulation. NDE1 recruits LIS1 to the dynein motor, where LIS1 induces a persistent force-producing state; NDE1 and dynactin form mutually exclusive complexes with dynein through overlapping binding sites on the dynein intermediate chain, enabling context-specific motor regulation [PMID:20403325, PMID:21911489, PMID:22669947]. CDK1 phosphorylation of NDE1 governs its cell-cycle-dependent localization to kinetochores (via CENP-F) and the nuclear envelope, its centrosomal stability, and G2-to-M progression, while CDK5-dependent priming targets NDE1 for FBW7-mediated ubiquitin-proteasomal degradation upon G1 entry to regulate primary cilia length [PMID:29930206, PMID:26206584, PMID:16682949]. Homozygous loss-of-function mutations in NDE1 that truncate the C-terminal dynein/LIS1/DISC1-binding domain cause severe microlissencephaly in humans, reflecting an essential role in neural progenitor proliferation, interkinetic nuclear migration, and cortical neurogenesis [PMID:21529751, PMID:21529752, PMID:15473967]."},"prefetch_data":{"uniprot":{"accession":"Q9NXR1","full_name":"Nuclear distribution protein nudE homolog 1","aliases":[],"length_aa":335,"mass_kda":37.7,"function":"Required for centrosome duplication and formation and function of the mitotic spindle. Essential for the development of the cerebral cortex. May regulate the production of neurons by controlling the orientation of the mitotic spindle during division of cortical neuronal progenitors of the proliferative ventricular zone of the brain. Orientation of the division plane perpendicular to the layers of the cortex gives rise to two proliferative neuronal progenitors whereas parallel orientation of the division plane yields one proliferative neuronal progenitor and a postmitotic neuron. A premature shift towards a neuronal fate within the progenitor population may result in an overall reduction in the final number of neurons and an increase in the number of neurons in the deeper layers of the cortex. Acts as a RAB9A/B effector that tethers RAB9-associated late endosomes to the dynein motor for their retrograde transport to the trans-Golgi network (PubMed:34793709)","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle; Cleavage furrow; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9NXR1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDE1","classification":"Not 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(nude) and euthymic mice: biochemical, histomorphometric, bone ash and in vitro studies.","date":"1989","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/2736153","citation_count":31,"is_preprint":false},{"pmid":"18203299","id":"PMC_18203299","title":"Anticancer activity of genistein on implanted tumor of human SG7901 cells in nude mice.","date":"2008","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18203299","citation_count":31,"is_preprint":false},{"pmid":"21725616","id":"PMC_21725616","title":"Cilengitide inhibits metastatic bone colonization in a nude rat model.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21725616","citation_count":31,"is_preprint":false},{"pmid":"23673330","id":"PMC_23673330","title":"Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23673330","citation_count":30,"is_preprint":false},{"pmid":"16322230","id":"PMC_16322230","title":"Point mutation at single tyrosine residue of novel oncogene NOK abrogates tumorigenesis in nude mice.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16322230","citation_count":30,"is_preprint":false},{"pmid":"6829300","id":"PMC_6829300","title":"Heterotransplantation of human head and neck tumours into nude mice.","date":"1983","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/6829300","citation_count":29,"is_preprint":false},{"pmid":"29930206","id":"PMC_29930206","title":"Cdk1 phosphorylation of the dynein adapter Nde1 controls cargo binding from G2 to anaphase.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29930206","citation_count":28,"is_preprint":false},{"pmid":"14688063","id":"PMC_14688063","title":"Regulation of chronic colitis in athymic nu/nu (nude) mice.","date":"2004","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14688063","citation_count":28,"is_preprint":false},{"pmid":"12016512","id":"PMC_12016512","title":"Complete rescue of the nude mutant phenotype by a wild-type Foxn1 transgene.","date":"2002","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/12016512","citation_count":27,"is_preprint":false},{"pmid":"29191162","id":"PMC_29191162","title":"Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29191162","citation_count":25,"is_preprint":false},{"pmid":"25332407","id":"PMC_25332407","title":"Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility.","date":"2014","source":"Schizophrenia bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/25332407","citation_count":25,"is_preprint":false},{"pmid":"23547542","id":"PMC_23547542","title":"Cyclosporin A reduces matrix metalloproteinases and collagen expression in dermal fibroblasts from regenerative FOXN1 deficient (nude) mice.","date":"2013","source":"Fibrogenesis & tissue repair","url":"https://pubmed.ncbi.nlm.nih.gov/23547542","citation_count":22,"is_preprint":false},{"pmid":"2330081","id":"PMC_2330081","title":"Growth of human schwannomas in the subrenal capsule of the nude mouse.","date":"1990","source":"Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/2330081","citation_count":21,"is_preprint":false},{"pmid":"3488965","id":"PMC_3488965","title":"Induction of early-phase endotoxin tolerance in athymic (nude) mice, B-cell-deficient (xid) mice, and splenectomized mice.","date":"1986","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/3488965","citation_count":21,"is_preprint":false},{"pmid":"6522098","id":"PMC_6522098","title":"Immunity to Brugia pahangi in athymic nude and normal mice: eosinophilia, antibody and hypersensitivity responses.","date":"1984","source":"Parasite immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6522098","citation_count":20,"is_preprint":false},{"pmid":"28462782","id":"PMC_28462782","title":"Regeneration of subcutaneous tissue-engineered mandibular condyle in nude mice.","date":"2017","source":"Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/28462782","citation_count":20,"is_preprint":false},{"pmid":"23116202","id":"PMC_23116202","title":"nde1 deletion improves mitochondrial DNA maintenance in Saccharomyces cerevisiae coenzyme Q mutants.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23116202","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43637,"output_tokens":6107,"usd":0.111258},"stage2":{"model":"claude-opus-4-6","input_tokens":9697,"output_tokens":4191,"usd":0.22989},"total_usd":0.341148,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Nde1 (mNudE) is essential for centrosome duplication and mitotic spindle assembly in cortical progenitors; Nde1 ablation in mouse causes defects in mitotic progression, mitotic orientation, and mitotic chromosome localization, resulting in reduced progenitor cell division and altered neuronal cell fates leading to microcephaly.\",\n      \"method\": \"Mouse knockout (Nde1-null), BrdU birthdating, in vitro centrosome duplication and spindle assembly assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype replicated in vivo and validated by in vitro assays\",\n      \"pmids\": [\"15473967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NudE (NDE1) stably recruits LIS1 to the dynein holoenzyme, where LIS1 interacts with the motor domain during the prepowerstroke state. NudE alone abrogates dynein force production, whereas LIS1 alone or with NudE induces a persistent-force dynein state that enhances ensemble function of multiple dyneins under high-load conditions.\",\n      \"method\": \"Single-molecule optical trapping assays, biochemical reconstitution with purified proteins, force measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with force measurements, mechanistic dissection of dynein states\",\n      \"pmids\": [\"20403325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nde1 localizes to the mother centriole and functions as a negative regulator of ciliary length. Nde1 is expressed at high levels in mitosis and low levels in quiescence; cells depleted of Nde1 have longer cilia and a delay in cell cycle re-entry that correlates with ciliary length.\",\n      \"method\": \"Nde1 knockdown (siRNA/shRNA), immunofluorescence localization, zebrafish morpholino knockdown, cell cycle re-entry assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, live imaging, in vivo zebrafish), strong phenotypic-mechanistic link\",\n      \"pmids\": [\"21394081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human NDE1 C-terminal domain is required for interaction with cytoplasmic dynein and for cell-cycle-dependent phosphorylation by Cdk1 at T246. Patient frameshift mutations truncating the C-terminus render NDE1 proteins unstable, unable to bind dynein, and unable to localize to the centrosome. CDK1 phosphorylation at T246 is required for cell-cycle progression from G2 to M phase.\",\n      \"method\": \"Patient cell lines, transfection of tagged NDE1 constructs, co-immunoprecipitation, immunofluorescence, CDK1 phosphorylation assays, cell cycle analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient cells, functional rescue experiments, kinase assays\",\n      \"pmids\": [\"21529751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NDE1 mutation (c.684_685del) results in a protein unable to localize to the centrosome. NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis; NDE1 deficiency causes severe failure of neurogenesis and deficiency in cortical lamination.\",\n      \"method\": \"Patient-derived cell lines, immunofluorescence, transfection of tagged NDE1 constructs, human and mouse embryonic brain staining\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient cells with multiple orthogonal localization and functional assays\",\n      \"pmids\": [\"21529752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cenp-F interacts with both Ndel1 and Nde1 and recruits them (along with Lis1) to kinetochores. Nde1 (but not Ndel1) is required for kinetochore localization of Dynein. Suppression of Nde1 inhibits metaphase chromosome alignment and activates the spindle checkpoint.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, spindle checkpoint assays\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA with defined cellular phenotypes, clear functional distinction between NDE1 and NDEL1\",\n      \"pmids\": [\"17600710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NudE and NudEL each localize to mitotic kinetochores before dynein, dynactin, ZW10, and LIS1. Inhibition of NudE/NudEL causes metaphase arrest with misoriented chromosomes and defective microtubule attachment. Dynein (through its intermediate and light chains, not motor domain) interacts with NudE, and both dynein and dynactin are displaced from kinetochores by anti-NudE/NudEL antibody injection.\",\n      \"method\": \"Anti-NudE/NudEL antibody microinjection, immunofluorescence, co-immunoprecipitation, time-lapse imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody injection functional assay, Co-IP mapping of interaction domain, replicated by two independent groups\",\n      \"pmids\": [\"17682047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NDE1 and NDEL1 are membrane-associated and their depletion leads to complete loss of dynein from membranes and dispersal of Golgi and endocytic compartments. NDE1 and NDEL1 act upstream of LIS1 in dynein recruitment/activation on membranes; exogenous NDE1 or NDEL1 can rescue LIS1 depletion effects on Golgi organization.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, subcellular fractionation, organelle position assays, epistasis rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via rescue experiments, fractionation showing membrane association, multiple organelle readouts\",\n      \"pmids\": [\"20048338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nudel (NDEL1, the NDE1 paralog) is phosphorylated in M phase by Cdc2 and Erk1/2. Phosphorylation regulates cell-cycle-dependent distribution of Nudel and increases its binding to Lis1. A Nudel mutant incapable of binding Lis1 impairs poleward movement of dynein and dynein-mediated transport of kinetochore proteins to spindle poles. NudE (NDE1) is functionally related to Nudel in this context.\",\n      \"method\": \"Phospho-specific mutants, co-immunoprecipitation, live-cell imaging, in vitro kinase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay and functional mutant analysis; primary findings on NDEL1 but NDE1 comparative data included\",\n      \"pmids\": [\"12556484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NudE (NDE1) and dynactin bind to a common region within the dynein intermediate chain (IC) and compete for this site. NudE binds dynein through its LC8 and IC subunits. NudE and dynactin form mutually exclusive complexes with dynein, preventing dual regulation of individual dynein molecules.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, competitive binding experiments, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with competitive binding and mutagenesis demonstrating mutually exclusive interactions\",\n      \"pmids\": [\"21911489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LIS1 and Nde1 collaboratively regulate the fate of radial glial progenitors. Mice with allelic series of Lis1 and Nde1 double mutations show dose-dependent cortical size reduction and delamination. Lis1-Nde1 deficiency alters metaphase progenitor morphology, reducing apical attachment and lateral contacts, which disrupts asymmetric cell division and causes premature neuronal differentiation.\",\n      \"method\": \"Double-mutant mouse genetics (epistasis), immunohistochemistry, BrdU/EdU birthdating, confocal imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with allelic series, strong dose-dependent phenotype\",\n      \"pmids\": [\"18469343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nde1 forms a complex with the centrosomal protein Su48. Nde1 is phosphorylated by Cdc2 in vivo at six putative sites; mutation of these sites diminishes phosphorylation, affects stability of Su48-Nde1 interactions, and affects centrosomal localization of Nde1. Ablation of Nde1 by siRNA causes mitotic delay and cell death.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro Cdc2 kinase assay, phospho-site mutagenesis, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase assay with mutagenesis, Y2H confirmed by Co-IP, functional siRNA phenotype\",\n      \"pmids\": [\"16682949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nde1 associates with p78/MCRS1 (a protein with a forkhead-associated domain) at the centrosome. The association between p78 and Nde1 is regulated by phosphorylation on Nde1. Abrogation of p78 by siRNA causes cell death and mitotic delay.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP confirmed interaction, functional siRNA; single lab\",\n      \"pmids\": [\"16547491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1, NDE1, NDEL1, LIS1, dynein, PDE4B, and PDE4D associate together in a centrosomal complex in mammalian cells. NDE1 is phosphorylated by PKA at a novel site. This DISC1-PDE4 modulated complex is present at the centrosome, and NDE1/NDEL1/LIS1 complex is proposed to localize at synapses.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, phospho-site mapping, synaptic localization in cultured neurons\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and localization data; single lab, multiple readouts\",\n      \"pmids\": [\"18983980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DISC1 and PDE4 modulate NDE1 phosphorylation by PKA at threonine-131 (T131). Phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions. T131-phosphorylated NDE1 is enriched at the centrosome during mitosis. Mutation mimicking PKA phosphorylation at T131 inhibits neurite outgrowth.\",\n      \"method\": \"Homology modeling, co-immunoprecipitation, phospho-specific antibody, neurite outgrowth assay, immunofluorescence\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phospho-site mutagenesis validated by Co-IP and functional assay; single lab\",\n      \"pmids\": [\"21677187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NDE1 protein levels are regulated by the E3 ubiquitin ligase FBW7 in a CDK5-dependent manner upon G1 entry. CDK5 primes NDE1 for FBW7-mediated recognition and destruction. Cells depleted of FBW7 or CDK5 show elevated NDE1 levels and reduced ciliary length, which is corrected by simultaneous NDE1 depletion, establishing a CDK5-FBW7-NDE1 pathway controlling ciliary length.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitylation assays, cell cycle synchronization, cilia length measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ubiquitylation assay identifying E3 ligase, CDK5 priming, epistasis rescue; multiple orthogonal methods\",\n      \"pmids\": [\"26206584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDE1 RNAi in embryonic rat brains causes cell cycle arrest of neural progenitors at three distinct stages: during apical interkinetic nuclear migration, at G2-to-M transition, and in regulation of primary cilia at G1-to-S transition. NDEL1 RNAi does not recapitulate these mitotic arrest phenotypes, revealing a unique NDE1 role at G2-to-M, though NDEL1 overexpression can compensate for NDE1 at other stages.\",\n      \"method\": \"In utero electroporation of shRNA, immunofluorescence, time-lapse imaging, cell cycle stage markers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in utero electroporation with defined stage-specific phenotypes, NDE1 vs NDEL1 dissection\",\n      \"pmids\": [\"27553190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NDE1 has a nuclear pool that interacts with cohesin and its associated chromatin remodeler. Loss of Nde1 causes DNA double-strand breaks during mid-late S phase at heterochromatin domains, activating p53-dependent apoptosis. This reveals a role for NDE1 in safeguarding heterochromatin replication during S phase.\",\n      \"method\": \"Co-immunoprecipitation (Nde1-cohesin), immunofluorescence (DNA damage markers), FACS cell cycle analysis, Nde1 mutant neural progenitors\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifying novel nuclear interaction, DSB phenotype in mutant cells; single lab, relatively new finding\",\n      \"pmids\": [\"25245017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Full-length NDE1 forms dimers, tetramers, and chain-like end-to-end polymers in solution. The C-terminal domain adopts a bent-back structure allowing it to interact with the N-terminal coiled-coil domain. NDE1 and NDEL1 can form mixed complexes. The C-terminal region (disrupted by disease mutations) is required for interaction with dynein and DISC1.\",\n      \"method\": \"Negative stain electron microscopy, chemical cross-linking/mass spectrometry, isotope labeling, homology modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural characterization with multiple orthogonal biophysical methods\",\n      \"pmids\": [\"22843697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The NDE1 N-terminal domain (forming a dimeric coiled-coil) interacts with the N-terminal domain of dynein intermediate chain (IC). NudE binds region 1 of the bi-segmental IC binding footprint used by p150(Glued)/dynactin, and when all three proteins are in solution, IC preferentially binds p150(Glued) despite NudE having higher affinity for the common segment alone.\",\n      \"method\": \"Isothermal titration calorimetry, NMR spectroscopy, competition binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — ITC and NMR with mutagenesis-level precision for interaction mapping\",\n      \"pmids\": [\"22669947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Nde1-Lis1 complex directly interacts with Brap, a MAPK signaling threshold modulator. Nde1-Lis1 deficiency causes spatially dependent hyperactivation of MAPK via altered Ksr scaffold; epistasis analyses support synergistic Brap and Lis1 functions in regulating cell fate decisions based on geographic proximity to midline signaling centers.\",\n      \"method\": \"Co-immunoprecipitation, double-mutant epistasis in mouse, immunofluorescence of MAPK pathway components\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and in vivo epistasis; single lab but multiple approaches\",\n      \"pmids\": [\"23673330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nde1 directly interacts with utrophin/dystrophin, allowing assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of radial glial cells (RGCs). Lis1-Nde1 mutations destabilize the dystrophin glycoprotein complex (DGC) and deform RGCs, disrupting basal lamina, RGC self-renewal, and neuronal migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, mouse genetics (Lis1-Nde1 mutants), genetic interaction with dystroglycan\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifying novel interaction, mouse genetics with epistasis; single lab\",\n      \"pmids\": [\"22028625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDE1 and dynactin form mutually exclusive complexes with dynein and exhibit non-overlapping distributions in T cells. NDE1/dynein complex mediates MTOC translocation to the immunological synapse, while dynactin/dynein complex mediates lytic granule transport. Dominant-negative NDE1 or NDE1 knockdown inhibits MTOC translocation and CTL-mediated killing.\",\n      \"method\": \"Dominant-negative NDE1 expression, siRNA knockdown in Jurkat and primary CTLs, immunofluorescence, killing assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional dissection of NDE1 vs dynactin roles with KD and DN constructs; single lab\",\n      \"pmids\": [\"27534551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The high-resolution crystal structure of DISC1 C-terminal tail in complex with the Ndel1 binding domain was solved. DISC1 regulates Ndel1/Nde1 kinetochore attachment (but not centrosome localization) during mitosis. Disrupting DISC1/Ndel1 complex formation prolongs mitotic length and causes cell-cycle deficits in human cells, mouse embryonic cortex, and human forebrain organoids.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, DISC1 mutant overexpression, in utero electroporation, cerebral organoids from patient iPSCs\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with multiple functional assays across model systems\",\n      \"pmids\": [\"29103808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK1 phosphorylates Nde1 in a cell cycle-dependent manner; phospho-Nde1 associates specifically with late G2-M nuclear envelope and prophase-to-anaphase kinetochores, mirroring CENP-F localization. Phosphomutant-Nde1 shows weaker CENP-F binding in vitro, establishing CENP-F as the first characterized Nde1 cargo protein. Expression of a dynein-binding-deficient Nde1 mutant reduces kinetochore dynein by half.\",\n      \"method\": \"NDE1 RNAi, phospho-specific antibody, phosphomimetic/phosphomutant cDNAs, in vitro binding assays, kinetochore dynein quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding assays with phosphomutants, phospho-specific antibody, functional RNAi phenotypes\",\n      \"pmids\": [\"29930206\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDE1 is a centrosomal scaffold protein that recruits LIS1 to cytoplasmic dynein to induce a persistent force-producing motor state, coordinates dynein localization to kinetochores (via CENP-F) and membranes in a CDK1/CDK5/PKA phosphorylation-dependent manner, negatively regulates primary cilia length through a CDK5-FBW7 ubiquitin-mediated degradation pathway, and is essential for neural progenitor cell-cycle progression (at IKN migration, G2-M, and G1-S transitions) and heterochromatin replication during S phase, with its C-terminal domain mediating interactions with dynein, LIS1, DISC1, and CENP-F that are disrupted by disease-causing truncation mutations.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NDE1 is a centrosomal and kinetochore scaffold protein that coordinates cytoplasmic dynein localization, activation, and force production across multiple cellular contexts including mitotic spindle assembly, chromosome alignment, membrane trafficking, and primary cilia regulation. NDE1 recruits LIS1 to the dynein motor, where LIS1 induces a persistent force-producing state; NDE1 and dynactin form mutually exclusive complexes with dynein through overlapping binding sites on the dynein intermediate chain, enabling context-specific motor regulation [PMID:20403325, PMID:21911489, PMID:22669947]. CDK1 phosphorylation of NDE1 governs its cell-cycle-dependent localization to kinetochores (via CENP-F) and the nuclear envelope, its centrosomal stability, and G2-to-M progression, while CDK5-dependent priming targets NDE1 for FBW7-mediated ubiquitin-proteasomal degradation upon G1 entry to regulate primary cilia length [PMID:29930206, PMID:26206584, PMID:16682949]. Homozygous loss-of-function mutations in NDE1 that truncate the C-terminal dynein/LIS1/DISC1-binding domain cause severe microlissencephaly in humans, reflecting an essential role in neural progenitor proliferation, interkinetic nuclear migration, and cortical neurogenesis [PMID:21529751, PMID:21529752, PMID:15473967].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that phosphorylation of the NDE1 paralog NDEL1 by Cdc2 and Erk1/2 regulates its binding to LIS1 and dynein-dependent kinetochore transport framed the paradigm that cell-cycle kinases control the NDE1/NDEL1–LIS1–dynein axis.\",\n      \"evidence\": \"Phospho-site mutagenesis, Co-IP, and live-cell imaging in mammalian cells focused on NDEL1 with comparative NDE1 data\",\n      \"pmids\": [\"12556484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary data are on NDEL1; NDE1-specific phosphoregulation not independently dissected\", \"In vivo relevance of individual phospho-sites for NDE1 unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that Nde1 knockout in mice causes microcephaly through failed centrosome duplication, spindle assembly, and mitotic progression in cortical progenitors established NDE1 as essential for brain size determination.\",\n      \"evidence\": \"Nde1-null mouse, BrdU birthdating, in vitro centrosome duplication and spindle assays\",\n      \"pmids\": [\"15473967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking NDE1 to centrosome duplication not identified\", \"Whether NDE1 acts solely through dynein in this context was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of NDE1 as a Cdc2 substrate at multiple sites and as an interactor of centrosomal Su48 and p78/MCRS1 defined NDE1 as a phospho-regulated centrosomal hub whose loss causes mitotic delay and cell death.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro Cdc2 kinase assay, phospho-site mutagenesis, siRNA knockdown\",\n      \"pmids\": [\"16682949\", \"16547491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of individual Cdc2 phospho-sites on NDE1 not fully resolved\", \"Whether Su48 and p78 interactions are direct or bridged through a common complex unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that NDE1 (but not NDEL1) is specifically required for dynein recruitment to kinetochores via CENP-F, and that NDE1/NDEL1 arrive at kinetochores before dynein, established NDE1 as a kinetochore-targeting adaptor for the dynein motor.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, antibody microinjection, immunofluorescence timing, spindle checkpoint assays\",\n      \"pmids\": [\"17600710\", \"17682047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NDE1–CENP-F binding interface not mapped\", \"Mechanism by which NDE1 recruits dynein to kinetochores (vs. stabilizes it there) unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Double-mutant epistasis with LIS1 and NDE1 allelic series demonstrated dose-dependent collaboration in radial glial progenitor fate, linking the NDE1–LIS1 axis to asymmetric cell division and cortical lamination.\",\n      \"evidence\": \"Lis1/Nde1 compound mutant mice, BrdU/EdU birthdating, confocal imaging\",\n      \"pmids\": [\"18469343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the dose-dependent effect reflects a threshold of dynein activity or independent NDE1–LIS1 functions unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Single-molecule force measurements revealed that NDE1 recruits LIS1 to dynein and that together they induce a persistent-force motor state, providing the first biophysical mechanism for NDE1 function in high-load transport.\",\n      \"evidence\": \"Optical trapping with purified dynein, NDE1, and LIS1 proteins; biochemical reconstitution\",\n      \"pmids\": [\"20403325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the persistent-force state operates identically in vivo under cargo-load conditions untested\", \"Role of NDE1 phosphorylation in modulating force production not examined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"NDE1/NDEL1 were shown to be membrane-associated and required upstream of LIS1 for all dynein recruitment to Golgi and endosomal membranes, extending NDE1's adaptor role beyond kinetochores to organelle positioning.\",\n      \"evidence\": \"siRNA knockdown, subcellular fractionation, organelle dispersal assays, epistasis rescue of LIS1 depletion\",\n      \"pmids\": [\"20048338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NDE1 itself is targeted to membranes not identified\", \"Relative contributions of NDE1 versus NDEL1 at membranes not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple discoveries converged to define NDE1 as a cilia-length regulator, a dynein IC/dynactin-competing adaptor, a PKA/DISC1 signaling target, and the gene mutated in human microlissencephaly, revealing the breadth of NDE1 functions in cell cycle and brain development.\",\n      \"evidence\": \"Cilia length measurements after Nde1 KD and zebrafish morpholinos [PMID:21394081]; competitive binding assays showing NDE1 and dynactin are mutually exclusive on dynein IC [PMID:21911489]; patient cell lines with C-terminal truncations showing loss of dynein binding and centrosome localization [PMID:21529751, PMID:21529752]; PKA phosphorylation at T131 modulating NDE1–LIS1 interaction and neurite outgrowth [PMID:21677187]; NDE1–utrophin/DGC interaction in radial glia [PMID:22028625]\",\n      \"pmids\": [\"21394081\", \"21911489\", \"21529751\", \"21529752\", \"21677187\", \"22028625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ciliary NDE1 function relates mechanistically to its centrosomal dynein role not resolved\", \"Structural basis for mutual exclusivity of NDE1 and dynactin on dynein IC not determined\", \"NDE1–utrophin interaction lacks independent replication\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structural studies showed NDE1 forms dimers, tetramers, and end-to-end polymers with a bent-back C-terminal domain, and that the NDE1 N-terminal coiled-coil binds dynein IC at a site overlapping with p150Glued, providing an atomic-level explanation for the competitive NDE1/dynactin relationship.\",\n      \"evidence\": \"Negative-stain EM, chemical cross-linking/mass spectrometry, ITC, NMR spectroscopy\",\n      \"pmids\": [\"22843697\", \"22669947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution crystal structure of the full NDE1–dynein complex\", \"Functional significance of NDE1 polymerization in vivo unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that the NDE1–LIS1 complex interacts with BRAP and modulates MAPK signaling thresholds revealed a signaling role for NDE1 beyond cytoskeletal motor regulation.\",\n      \"evidence\": \"Co-IP, double-mutant epistasis in mouse with MAPK pathway readouts\",\n      \"pmids\": [\"23673330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NDE1–BRAP interaction is direct or LIS1-mediated not resolved\", \"Not independently replicated\", \"Mechanism of MAPK modulation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of a nuclear NDE1 pool that interacts with cohesin and safeguards heterochromatin replication during S phase revealed a non-centrosomal function for NDE1 in genome integrity.\",\n      \"evidence\": \"Co-IP of Nde1 with cohesin, DNA damage markers in Nde1-mutant neural progenitors, FACS cell cycle analysis\",\n      \"pmids\": [\"25245017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NDE1 acts directly in replication fork protection or indirectly through cohesin loading is unknown\", \"Nuclear NDE1 pool not independently replicated\", \"Relationship to dynein-dependent functions unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the CDK5–FBW7 ubiquitin-mediated degradation pathway for NDE1 at G1 entry established how cell-cycle-dependent NDE1 turnover controls cilia length and cell cycle re-entry.\",\n      \"evidence\": \"Ubiquitylation assays, CDK5 priming, epistasis rescue (FBW7 KD + NDE1 KD), cilia length measurements\",\n      \"pmids\": [\"26206584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also target NDE1 not explored\", \"How ciliary NDE1 is mechanistically linked to cilia disassembly or resorption not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In vivo dissection in embryonic rat brain revealed three distinct cell-cycle arrest points caused by NDE1 loss—interkinetic nuclear migration, G2-to-M, and G1-to-S (cilia)—that are not shared by NDEL1, and that NDE1/dynactin form functionally non-overlapping dynein complexes mediating MTOC translocation versus granule transport in T cells.\",\n      \"evidence\": \"In utero electroporation of shRNA with cell-cycle markers [PMID:27553190]; dominant-negative NDE1 and siRNA in CTLs with killing assays [PMID:27534551]\",\n      \"pmids\": [\"27553190\", \"27534551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NDE1 specifically licenses G2-to-M transition molecularly (beyond CDK1 phosphorylation) unresolved\", \"Whether NDE1's immune synapse role is relevant in vivo not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structure of the DISC1–NDEL1 complex and functional data showed DISC1 regulates NDE1/NDEL1 kinetochore attachment during mitosis; disruption of this complex prolongs mitosis and impairs cortical neurogenesis in organoids.\",\n      \"evidence\": \"X-ray crystallography, Co-IP, in utero electroporation, human cerebral organoids from patient iPSCs\",\n      \"pmids\": [\"29103808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure solved for NDEL1; whether DISC1–NDE1 interface is identical not confirmed crystallographically\", \"Contribution of DISC1–NDE1 versus DISC1–NDEL1 in human disease not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CDK1-phosphorylated NDE1 was shown to bind CENP-F directly, establishing CENP-F as the first characterized NDE1 cargo protein and explaining how phosphorylation gates NDE1 kinetochore localization and dynein recruitment.\",\n      \"evidence\": \"Phospho-specific antibody, phosphomimetic/phosphomutant in vitro binding assays, kinetochore dynein quantification after NDE1 RNAi\",\n      \"pmids\": [\"29930206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full phospho-code governing NDE1 localization across the cell cycle not mapped\", \"Whether CENP-F–NDE1 interaction is sufficient or whether additional kinetochore factors are needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include how NDE1's nuclear/cohesin role relates to its centrosomal dynein functions, what structural basis underlies NDE1 polymerization and its functional significance, and how context-specific kinase codes (CDK1, CDK5, PKA) are integrated to direct NDE1 to distinct subcellular destinations.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length NDE1 or NDE1–dynein complex\", \"Nuclear versus centrosomal NDE1 pools not mechanistically connected\", \"Integrated phospho-regulation model across CDK1, CDK5, and PKA lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 6, 7, 9, 24]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 6, 9, 18, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2, 3, 4, 11, 13]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5, 6, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3, 5, 6, 11, 16, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 10, 16, 23]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 20]}\n    ],\n    \"complexes\": [\n      \"NDE1–LIS1–dynein\",\n      \"DISC1–NDE1–NDEL1–PDE4\"\n    ],\n    \"partners\": [\n      \"LIS1\",\n      \"DYNC1H1\",\n      \"CENP-F\",\n      \"DISC1\",\n      \"NDEL1\",\n      \"DCTN1\",\n      \"FBXW7\",\n      \"UTRN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}