id: MODULE:nucleokinesis title: Nucleokinesis (motor-driven nuclear translocation) module description: >- Nucleokinesis is the directed translocation of the nucleus within a cell that is migrating or changing shape, most prominently in migrating neurons and in the interkinetic nuclear migration of neuroepithelial and radial glial progenitors. In migrating neurons it follows a two-stroke cycle: the centrosome and Golgi first advance into a swelling of the leading process, and the nucleus then moves forward toward them in a saltatory step. The nucleus is coupled to cytoplasmic motors through its envelope, either by LINC complexes (inner-nuclear-membrane SUN proteins bound to outer-nuclear-membrane KASH nesprins, with nesprin-2 recruiting dynein and kinesin through the adaptor BICD2) or, in G2 radial glial progenitors, by nuclear-pore-anchored dynein adaptors (RANBP2-BICD2 and NUP133-CENPF-NDE1/NDEL1). Cytoplasmic dynein, with dynactin and the LIS1-NDEL1/NDE1 regulatory module, pulls the nucleus toward microtubule minus ends at the centrosome along a perinuclear microtubule cage stabilized by doublecortin. Non-muscle myosin II contraction at the rear of the soma assists forward nuclear movement, and in progenitors the kinesin-3 KIF1A drives the opposite, basally directed nuclear movement. CDK5/p35 phosphorylation of NDEL1 links the core machinery to migration signaling. The same dynein-driven program also operates outside the central nervous system: trunk neural crest cells use it to pull their nucleus through confined tissue spaces. Loss of LIS1 or DCX causes lissencephaly, reflecting the dependence of cortical neuronal migration on this machinery. status: DRAFT scope: ABSTRACT evidence: - source_id: PMID:15882636 title: "Nucleokinesis in neuronal migration." statement: >- Review defining nucleokinesis as the cell-body/nuclear movement phase of neuronal migration and its dependence on dynein, polarity genes and microtubule-associated proteins positioned around the centrosome. supporting_text: >- These coordinate first the positioning of the centrosome (microtubule organizing center) in the leading process in front of the nucleus and then the movement of the nucleus towards the centrosome. - source_id: PMID:15173193 title: "Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration." statement: >- Establishes nucleus-centrosome coupling by LIS1, DCX and dynein as a core mechanism of neuronal nucleokinesis. supporting_text: >- These data indicate Lis1 and Dcx function with dynein to mediate N-C coupling during migration - source_id: PMID:19874786 title: "SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice." statement: >- Identifies LINC complexes as the nuclear-envelope link between dynein/kinesin motors and the nucleus in both interkinetic nuclear migration and radial neuronal migration. supporting_text: >- We show that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. - source_id: PMID:17618279 title: "Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue." statement: >- Live imaging shows that the nucleus is carried along centrosome-anchored microtubules by dynein with assistance from myosin II. supporting_text: >- The nucleus is transported along the trailing microtubules by dynein assisted by myosin II. - source_id: DOI:10.64898/2026.06.09.730088 title: "A dynein-driven nucleokinesis program enables neural crest migration through confined tissues in vivo" statement: >- Preprint (not peer reviewed) extending dynein-driven nucleokinesis to trunk neural crest cells migrating through confined tissue in zebrafish, where a centrosome-associated microtubule bundle ahead of the nucleus pulls and deforms it, independently of myosin II contractility. supporting_text: >- Microtubule-dependent nucleokinesis constitutes an evolutionarily conserved cellular program ensuring directional nucleus translocation by deployment of cytoplasmic dynein motors. notes: >- Boundary. The module covers the force-generating and force-transmitting machinery that moves the nucleus: nuclear-envelope coupling, the dynein motor with its LIS1/NDEL1 regulators, the perinuclear microtubule track, rear actomyosin contraction, and the plus-end kinesin used for basal interkinetic movement, plus CDK5/p35 as a directly acting regulator. Leading process extension, centrosome advance into the leading-process swelling (centrokinesis), PAR-polarity signaling, reelin signaling and cell adhesion to radial glia are treated as upstream or parallel neuronal-migration biology, not as parts of nucleokinesis itself. Nuclear positioning in muscle and fungal nuclear distribution use homologous machinery and are not modelled as variants. The fungal nuclear-distribution genes (NudF, NudE and NudA, from which the LIS1/NDE nomenclature derives) move nuclei along hyphae, or position the spindle through cortical dynein in budding yeast. C. elegans P-cell and hyp7 nuclear migration is modelled as the UNC-84/UNC-83 variant. Comparative and family reviews. Orthologs are reviewed under genes// (Aspergillus nudF/nudE/nudA, budding yeast PAC1/NDL1, worm lis-1/nud-2/ unc-83/unc-84, fly Lis-1/nudE/BicD/klar/koi). PANTHER family reviews are in interpro/panther/{PTHR10921,PTHR44129,PTHR31233,PTHR14514}/. - LIS1 and NudE orthologs in fungi, yeast, worm and fly all carry cytoskeletal motor regulator activity (GO:0140659), which supports the module's LIS1 and NudE units. No PAINT node asserts a regulator function for either family. - Fungal reconstitution data (NudF relieving dynein autoinhibition) lean toward the activator term GO:0140660. Yeast Pac1 is inhibitory at plus ends, so the regulator parent term stays. - In both fungi NudE is secondary: extra LIS1 bypasses its loss. - The NudE kinetochore and centrosome roles are animal-specific (fungi lack CENP-F). Centrosome residence is vertebrate-only: fly NudE is not centrosomal. The NudE PAINT kinetochore, centrosome and kinesin-complex IBDs are flagged for restriction or removal in the PTHR10921 review. - PANTHER groups LIS1 orthologs inconsistently. PTHR44129 is named after an unrelated F-box protein and mixes LIS1 with other WD40 proteins, and UniProt/InterPro cross-references scatter worm, yeast and zebrafish LIS1 into other families. The LIS1 unit therefore stays a single gene product rather than a family selector. - BICD adaptor and activator functions hold across the BICD family (PTHR31233). What attaches fly BicD to photoreceptor nuclei is unknown. Module deep research (modules/nucleokinesis-deep-research-falcon.md) agreed with this boundary and added the nesprin-2-BICD2 link, kinesin-1 antagonism, CDK1 timing of the pore route, and NDE1/NDEL1 dosage evidence, each checked against the primary papers before use. It also describes NDE1 as predominant in progenitor interkinetic migration and NDEL1 in postmitotic migration; the module keeps both under one NudE-family unit, with the partition stated in the unit's role (PMID:27553190, PMID:38194050). Gene-review reconciliation. All 17 members now have complete gene reviews (genes/human//). The module was reconciled with them: - CENPF uses protein-macromolecule adaptor activity (GO:0030674), not dynein complex binding, because it recruits dynein indirectly via NDE1/NDEL1. - BICD2 binds nesprin-2 at a site distinct from the kinesin-1 LEWD motif (PMID:39115447). - The direction of the kinesin-1 effect is cell-type dependent. - Nesprin-1 acts redundantly with nesprin-2 only in some brain regions. - DCTN1 and the NudE unit now carry function terms matching their reviews (GO:0140660, contributes_to via dynactin; GO:0140659). - The non-muscle myosin II paralog for neuronal rear contraction is left unresolved. Open terminology question from the reviews: whether LIS1 should carry cytoskeletal motor activator activity (GO:0140660) rather than the regulator parent. Term choices. GO:0007097 nuclear migration is used as the module core; GO:0021817 (nucleokinesis in radial glia-guided cortical migration) and GO:0022027 (interkinetic nuclear migration) are recorded as context-specific child processes. For the LINC complex, GOA annotates SUN1/SUN2/SYNE1/SYNE2 to GO:0034993 meiotic nuclear membrane microtubule tethering complex; the module uses its non-meiotic parent GO:0106094 because nucleokinesis occurs in interphase somatic cells. Exemplars are human UniProt entries; the key functional work cited was done in mouse and rat brain, cultured cerebellar granule neurons, MGE interneurons, zebrafish retina and zebrafish trunk neural crest. The neural crest evidence (DOI:10.64898/2026.06.09.730088) is a 2026 preprint that inhibited dynein with ciliobrevin D and with neural-crest-specific dynamitin overexpression; it did not test LINC, LIS1 or NDEL1 components, so their involvement in neural crest nucleokinesis is inferred, not shown. The same preprint reports dynein heavy chain enriched at the nuclear envelope of confined but not unconfined neural crest cells, and that unconfined cranial neural crest cells migrate without needing dynein, suggesting tissue confinement engages this program. The relative weight of dynein pulling versus actomyosin pushing differs between cell types (see the actomyosin part), and has not been resolved into a single general model. module: id: nucleokinesis label: Nucleokinesis module_type: BIOLOGICAL_PROCESS description: >- Motor-driven translocation of the nucleus toward the centrosome or along the apico-basal axis, built from nuclear-envelope motor coupling, a dynein-LIS1-NDEL1 minus-end motor, a DCX-stabilized perinuclear microtubule track, rear actomyosin contraction, basal kinesin-3 transport in progenitors, and CDK5/p35 regulation. concepts: - preferred_term: nuclear migration term: id: GO:0007097 label: nuclear migration description: >- Core process: directed movement of the nucleus to a specific location within the cell. - preferred_term: nuclear migration along microtubule term: id: GO:0030473 label: nuclear migration along microtubule description: >- The microtubule-motor-driven mode that carries most of the module's force generation. - preferred_term: nucleokinesis in radial glia-guided cortical migration term: id: GO:0021817 label: nucleokinesis involved in cell motility in cerebral cortex radial glia guided migration description: >- Context-specific child process for postmitotic neurons migrating radially along glial fibers. - preferred_term: interkinetic nuclear migration term: id: GO:0022027 label: interkinetic nuclear migration description: >- Context-specific child process for cell-cycle-coupled apico-basal nuclear movement in neuroepithelial and radial glial progenitors. context: taxa: - preferred_term: Metazoa term: id: NCBITaxon:33208 label: Metazoa description: >- Characterized mechanistically in vertebrate brain; the core dynein/LIS1/NudE and SUN-KASH machinery is conserved across eukaryotes with nuclear migration. cell_types: - preferred_term: migrating neuron description: >- Radially and tangentially migrating postmitotic neurons (cortical projection neurons, cerebellar granule neurons, MGE-derived interneurons). - preferred_term: radial glial / neuroepithelial progenitor description: >- Progenitors undergoing interkinetic nuclear migration. - preferred_term: migratory neural crest cell term: id: CL:0000333 label: migratory neural crest cell description: >- Trunk neural crest cells migrating through confined tissue spaces (zebrafish; preprint evidence). cellular_components: - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope - preferred_term: centrosome term: id: GO:0005813 label: centrosome - preferred_term: perinuclear region of cytoplasm term: id: GO:0048471 label: perinuclear region of cytoplasm parts: - order: 1 role: coupling the nucleus to cytoskeletal motors at the nuclear envelope node: id: nuclear_envelope_motor_coupling label: Nuclear-envelope motor coupling module_type: BIOLOGICAL_PROCESS description: >- Motors can only move the nucleus if they are anchored to its envelope. Two anchoring routes are established: LINC complexes that span both nuclear membranes, and nuclear-pore-anchored dynein adaptors used in G2 radial glial progenitors. Envelope coupling is required specifically for the nuclear stroke: when it is disrupted the nucleus stalls while the centrosome continues to advance. evidence: - source_id: PMID:32619477 title: "Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo." supporting_text: >- Although disruption of the Nesprin-2/BicD2 interaction severely inhibited nuclear movement, centrosome advance proceeded unimpeded, supporting an independent mechanism for centrosome advance. variant_sets: - id: nuclear_motor_anchoring_route label: Nuclear-envelope motor anchoring route axis: nuclear-envelope anchor (LINC complex vs nuclear pore complex) selection: ONE_OR_MORE notes: >- The routes are not mutually exclusive. LINC coupling is required in both postmitotic neurons and progenitors; the nuclear-pore routes have been shown specifically for G2 apical migration of radial glial progenitors, where RANBP2-BICD2 and NUP133-CENPF act sequentially. variants: - id: linc_complex_route label: LINC complex (SUN-KASH) coupling module_type: PROTEIN_COMPLEX description: >- Inner-nuclear-membrane SUN1/SUN2 trimers bind the KASH domains of outer-nuclear-membrane nesprins in the perinuclear space; the cytoplasmic domain of nesprin-2 binds the adaptor BICD2, which recruits dynein/dynactin and kinesin-1 to the nucleus. SUN1 and SUN2 act redundantly. Dynein-dynactin-BICD2 binds nesprin-2 at a site distinct from the adjacent kinesin-1-binding LEWD motif. The contribution of kinesin-1 is cell-type dependent: in rat cortical neurons its inhibition accelerates migration, whereas in mouse cerebellar granule neurons its inhibition reduces nuclear movement and both motor-binding sites of nesprin-2 are needed. The actin-binding domain of nesprin-2 is dispensable for cortical migration. evidence: - source_id: PMID:39115447 title: "Nesprin-2 coordinates opposing microtubule motors during nuclear migration in neurons." supporting_text: >- Nesprin-2 recruits dynein-dynactin-BicD2 independently of the nearby kinesin-binding LEWD motif. Both motor binding sites are required to rescue nuclear migration defects caused by the loss of function of Nesprin-2. - source_id: PMID:39115447 supporting_text: >- upon the inhibition of kinesin-1 by overexpression of Kif5B-tail or the tetratricopeptide repeat domain of kinesin light chain 1 (KLC1-TPR) concepts: - preferred_term: LINC complex term: id: GO:0106094 label: nuclear membrane microtubule tethering complex conforms_to: - template: linc_complex status: WITH_DEVIATIONS deviations: - SUN and KASH components are modelled as annotons of one node rather than as separate parts. - Only the nesprin-1/2 KASH variant is used; nesprin-3, nesprin-4 and KASH5 are not involved in nucleokinesis. - BICD2 is added as the nesprin-2-bound dynein adaptor, which the template treats as a cytoplasmic interface. - The SUN lamina-anchoring annoton and the torsinA regulatory part are not repeated here. notes: >- The general SUN-KASH bridge, its paralogs and complex-term choices are modelled in MODULE:linc_complex; this variant keeps only the nucleokinesis-specific motor coupling. annotons: - id: sun_inner_membrane_anchor label: SUN-domain inner nuclear membrane anchor participant: selector_type: FAMILY family: preferred_term: SUN-domain proteins (SUN1, SUN2) term: id: PANTHER:PTHR12911 label: SAD1/UNC-84-LIKE PROTEIN-RELATED representative_members: - preferred_term: SUN1 term: id: UniProtKB:O94901 label: SUN domain-containing protein 1 - preferred_term: SUN2 term: id: UniProtKB:Q9UH99 label: SUN domain-containing protein 2 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane role_description: >- Spans the inner nuclear membrane and binds nesprin KASH domains in the perinuclear space, transmitting cytoplasmic motor force to the nuclear lamina. evidence: - source_id: PMID:19874786 supporting_text: >- We show that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. - id: kash_nesprin_motor_adaptor label: KASH-domain nesprin outer nuclear membrane motor adaptor participant: selector_type: FAMILY family: preferred_term: KASH-domain nesprins (nesprin-1, nesprin-2) term: id: PANTHER:PTHR14514 label: PKA ANCHORING PROTEIN representative_members: - preferred_term: SYNE2 (nesprin-2) term: id: UniProtKB:Q8WXH0 label: Nesprin-2 - preferred_term: SYNE1 (nesprin-1) term: id: UniProtKB:Q8NF91 label: Nesprin-1 ancestral_nodes: - preferred_term: PAINT node PTN009019575 (nesprin-1/2 clade) term: id: PANTHER:PTN009019575 label: PTN009019575 description: >- Asserts nuclear migration (GO:0007097) and centrosome localization (GO:0051642) for the KASH-bearing nesprin-1/2 clade; both hold in the PTHR14514 family review, which also notes the family contains KASH-less AKAP6. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN009019575 in PTHR14514. - source_id: file:interpro/panther/PTHR14514/PTHR14514-review.yaml statement: Family review assessing the nesprin/AKAP6 PAINT nodes. function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: cytoplasmic dynein-dynactin - preferred_term: kinesin-1 locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane role_description: >- Outer-nuclear-membrane KASH protein whose cytoplasmic domain recruits dynein/dynactin and kinesin, connecting the nucleus to the centrosome-anchored microtubule array. Nesprin-2 is essential in the cerebral cortex and hippocampus; nesprin-1 acts redundantly with it only in the cerebellum, midbrain and hindbrain, and its motor link has not been resolved to a specific isoform. evidence: - source_id: PMID:19874786 supporting_text: >- Syne-2 is connected to the centrosome through interactions with both dynein/dynactin and kinesin complexes. - source_id: PMID:19874786 supporting_text: >- These results indicate that Syne-2 alone is essential for the laminary structure formation in both the cerebral cortex and hippocampus, and that Syne-1 and Syne-2 have redundant roles in the cerebellum, midbrain, brain stem and other brain regions. - source_id: PMID:32619477 supporting_text: >- We find that an ∼100-kDa "mini" form of the ∼800-kDa Nesprin-2 protein, which binds dynein and kinesin, is sufficient, remarkably, to support neuronal migration. - id: bicd2_nesprin_motor_adaptor label: BICD2 nesprin-2-bound dynein/kinesin adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BICD2 term: id: UniProtKB:Q8TD16 label: Protein bicaudal D homolog 2 function: preferred_term: cytoskeletal adaptor activity term: id: GO:0008093 label: cytoskeletal adaptor activity targets: - preferred_term: cytoplasmic dynein-dynactin - preferred_term: kinesin-1 - preferred_term: nesprin-2 (dynein-adaptor-binding region, distinct from the kinesin-1 LEWD motif) locations: - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope role_description: >- Bound to nesprin-2, BICD2 recruits dynein-dynactin to the LINC complex in postmitotic neurons; kinesin-1 binds nesprin-2 separately at the LEWD motif. BICD2 is also a dynein activating adaptor (cytoskeletal motor activator activity, GO:0140660, asserted in its gene review), and the same adaptor is used by the G2 nuclear-pore route. evidence: - source_id: PMID:32619477 supporting_text: >- We find further that, surprisingly, the motor proteins interact with Nesprin-2 through the dynein/kinesin "adaptor" BicD2, both in neurons and in non-mitotic fibroblasts. - source_id: PMID:39115447 supporting_text: >- Nesprin-2 recruits dynein-dynactin-BicD2 independently of the nearby kinesin-binding LEWD motif. - source_id: PMID:32619477 supporting_text: >- In contrast to dynein's role in forward nuclear migration in these cells, we find that kinesin-1 inhibition accelerates neuronal migration, suggesting a novel role for the opposite-directed motor proteins in regulating migration velocity. - id: worm_unc84_unc83_route label: C. elegans UNC-84/UNC-83 motor hub (P cells, hyp7 precursors) module_type: PROTEIN_COMPLEX description: >- In C. elegans, the SUN protein UNC-84 anchors the KASH protein UNC-83. UNC-83 recruits kinesin-1 (through KLC-2) and the dynein regulators NUD-2/LIS-1, BICD-1 and DLC-1, so that nuclei migrate through constrictions in P cells and hyp7 precursors. The motor balance differs from neuronal nucleokinesis: in hyp7 precursors kinesin-1 carries the nucleus toward microtubule plus ends and dynein mainly regulates the movement. The general bridge is modelled in MODULE:linc_complex (worm UNC-83 variant). annotons: - id: unc83_nuclear_motor_hub label: UNC-83 nuclear motor hub participant: selector_type: GENE_PRODUCT gene_product: preferred_term: unc-83 (C. elegans) term: id: UniProtKB:Q23064 label: Nuclear migration protein unc-83 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: UNC-84 (SUN) - preferred_term: kinesin-1 (KLC-2) - preferred_term: NUD-2/LIS-1, BICD-1, DLC-1 processes: - preferred_term: nuclear migration along microtubule term: id: GO:0030473 label: nuclear migration along microtubule locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:27697906 supporting_text: >- The LINC complex, consisting of the SUN protein UNC-84 and the KASH protein UNC-83, recruits dynein and kinesin-1 to the nuclear surface. - source_id: PMID:20005871 supporting_text: >- These data demonstrate that UNC-83 recruits NUD-2 to the nuclear envelope through a direct interaction in vivo. - id: nuclear_pore_dynein_recruitment_route label: Nuclear-pore dynein recruitment (G2 progenitors) module_type: BIOLOGICAL_PROCESS description: >- In G2 radial glial progenitors, dynein is recruited to the nuclear surface by two sequential nuclear-pore pathways: RANBP2 recruits BICD2, which binds dynein and dynactin; later, NUP133 recruits CENPF, which recruits NDE1/NDEL1 and thereby dynein and LIS1. Both are required for apical nuclear migration before mitosis. The routes are switched on in G2 by CDK1: CDK1 and PLK1 phosphorylation activates BICD2 and favours its binding to CDK1-phosphorylated RANBP2, and CDK1 sites on NDE1 (T215, T243) are required for apical migration. evidence: - source_id: PMID:24034252 title: "Dynein recruitment to nuclear pores activates apical nuclear migration and mitotic entry in brain progenitor cells." supporting_text: >- The "RanBP2-BicD2" and "Nup133-CENP-F" pathways act sequentially, with Nup133 or CENP-F RNAi arresting nuclei close to the ventricular surface in a premitotic state. - source_id: PMID:37105961 title: "BICD2 phosphorylation regulates dynein function and centrosome separation in G2 and M." statement: >- Mechanism for G2 activation of the RANBP2-BICD2 route, characterized in cultured non-neural cells. supporting_text: >- Moreover, modified BICD2 preferentially interacts with the nucleoporin RanBP2 once RanBP2 has been phosphorylated by CDK1. - source_id: PMID:39167527 title: "The Role of Nde1 phosphorylation in interkinetic nuclear migration and neural migration during cortical development." supporting_text: >- We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. annotons: - id: bicd2_nuclear_pore_dynein_adaptor label: BICD2 nuclear-pore dynein adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BICD2 term: id: UniProtKB:Q8TD16 label: Protein bicaudal D homolog 2 function: preferred_term: cytoskeletal adaptor activity term: id: GO:0008093 label: cytoskeletal adaptor activity targets: - preferred_term: cytoplasmic dynein-dynactin - preferred_term: RANBP2 (nucleoporin Nup358) locations: - preferred_term: nuclear envelope (cytoplasmic face of nuclear pores) term: id: GO:0005635 label: nuclear envelope role_description: >- Bound to RANBP2 at the cytoplasmic face of nuclear pores, BICD2 recruits dynein and dynactin to the nuclear surface in G2. evidence: - source_id: PMID:24034252 supporting_text: >- The nucleoporin RanBP2 recruits BicD2, which, in turn, recruits both cytoplasmic dynein and its regulatory complex dynactin to the nuclear surface - source_id: PMID:20386726 title: "Bicaudal D2, dynein, and kinesin-1 associate with nuclear pore complexes and regulate centrosome and nuclear positioning during mitotic entry." statement: >- Original characterization of RANBP2-bound BICD2 as a G2 nuclear-pore adaptor for dynein and kinesin-1 in non-neural cultured cells. - id: cenpf_nuclear_pore_nude_recruiter label: CENPF nuclear-pore NDE1/NDEL1 recruiter participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CENPF term: id: UniProtKB:P49454 label: Centromere protein F function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity description: >- Recruited to pores by NUP133, CENPF recruits NDE1/NDEL1, which in turn bind dynein and LIS1. CENPF recruits dynein indirectly, so a direct dynein-binding term is not asserted (GOA's GO:0070840 row is UNDECIDED in the CENPF review). targets: - preferred_term: NUP133 - preferred_term: NDE1/NDEL1 locations: - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope evidence: - source_id: PMID:24034252 supporting_text: >- CENP-F, in turn, recruits NudE and NudEL, each of which bind directly to cytoplasmic dynein and its regulator LIS1 - source_id: PMID:21383080 title: "A Nup133-dependent NPC-anchored network tethers centrosomes to the nuclear envelope in prophase." supporting_text: >- Recent studies have demonstrated a role for CENP-F in indirectly recruiting dynein/dynactin to kinetochores via NudE and/or NudEL - order: 2 role: minus-end-directed force generation pulling the nucleus toward the centrosome node: id: dynein_lis1_nude_motor label: Dynein-dynactin-LIS1-NDEL1 nuclear motor module_type: PROTEIN_COMPLEX description: >- Cytoplasmic dynein, activated by dynactin and regulated by LIS1 and its NudE-family partners NDEL1/NDE1, walks toward microtubule minus ends anchored at the centrosome and so pulls the envelope-coupled nucleus forward. The same motor drives apical (G2) interkinetic nuclear migration in progenitors. LIS1 and dynein also act at the leading-process swelling to advance the centrosome, a separable centrokinesis role outside this module. concepts: - preferred_term: cytoplasmic dynein complex term: id: GO:0005868 label: cytoplasmic dynein complex annotons: - id: dynein_nuclear_motor label: Cytoplasmic dynein-1 motor with LIS1/NDEL1 regulators participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: cytoplasmic dynein-1 with dynactin, LIS1 and NDEL1/NDE1 active_units: - id: dync1h1_motor_unit label: Dynein-1 heavy chain motor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DYNC1H1 term: id: UniProtKB:Q14204 label: Cytoplasmic dynein 1 heavy chain 1 role: ATP-driven minus-end-directed motor function: preferred_term: minus-end-directed microtubule motor activity term: id: GO:0008569 label: minus-end-directed microtubule motor activity - id: dynactin_unit label: Dynactin (p150Glued/DCTN1) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DCTN1 (p150Glued) term: id: UniProtKB:Q14203 label: Dynactin subunit 1 role: dynein activator and processivity factor (acts as part of the dynactin complex) function: preferred_term: cytoskeletal motor activator activity term: id: GO:0140660 label: cytoskeletal motor activator activity - id: lis1_unit label: LIS1 dynein regulator participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PAFAH1B1 (LIS1) term: id: UniProtKB:P43034 label: Platelet-activating factor acetylhydrolase IB subunit beta role: binds the dynein motor domain and regulates its force production function: preferred_term: cytoskeletal motor regulator activity term: id: GO:0140659 label: cytoskeletal motor regulator activity - id: nude_unit label: NudE-family LIS1-dynein scaffold participant: selector_type: FAMILY family: preferred_term: NudE family (NDEL1, NDE1) term: id: PANTHER:PTHR10921 label: NUCLEAR DISTRIBUTION PROTEIN NUDE HOMOLOG 1 representative_members: - preferred_term: NDEL1 term: id: UniProtKB:Q9GZM8 label: Nuclear distribution protein nudE-like 1 - preferred_term: NDE1 term: id: UniProtKB:Q9NXR1 label: Nuclear distribution protein nudE homolog 1 role: >- tethers LIS1 to dynein, sustaining dynein function in nuclear translocation; NDE1 predominates in progenitors (apical interkinetic migration) and NDEL1 in postmitotic migrating neurons function: preferred_term: cytoskeletal motor regulator activity term: id: GO:0140659 label: cytoskeletal motor regulator activity function: preferred_term: minus-end-directed microtubule motor activity term: id: GO:0008569 label: minus-end-directed microtubule motor activity description: >- Motor activity resides in the dynein heavy chain; dynactin, LIS1 and NDEL1/NDE1 regulate it. processes: - preferred_term: nuclear migration along microtubule term: id: GO:0030473 label: nuclear migration along microtubule - preferred_term: interkinetic nuclear migration term: id: GO:0022027 label: interkinetic nuclear migration locations: - preferred_term: perinuclear region of cytoplasm term: id: GO:0048471 label: perinuclear region of cytoplasm - preferred_term: centrosome term: id: GO:0005813 label: centrosome evidence: - source_id: PMID:15473966 title: "Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning." supporting_text: >- These results provide strong evidence that Ndel1 interacts with LIS1 to sustain the function of dynein, which in turn impacts microtubule organization, nuclear translocation, and neuronal positioning. - source_id: PMID:11163259 title: "A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system." supporting_text: >- Here, we demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL, a murine homolog of the Aspergillus nidulans nuclear migration mutant NudE. - source_id: PMID:21037580 title: "Kinesin 3 and cytoplasmic dynein mediate interkinetic nuclear migration in neural stem cells." supporting_text: >- RNAi directed against cytoplasmic dynein specifically inhibited nuclear movement toward the apical surface. - source_id: PMID:16144905 title: "LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages." supporting_text: >- These results identify multiple distinct and novel roles for LIS1 in nucleokinesis and process dynamics - source_id: PMID:20007476 title: "Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice." supporting_text: >- Complete loss of Lis1 or Ndel1 resulted in the total inhibition of nuclear movement in cortical slice assays - source_id: PMID:27553190 title: "Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages." statement: >- NDE1, not NDEL1, is required for apical interkinetic nuclear migration in rat radial glia, while both act in postmitotic neuronal migration. supporting_text: >- RNAi against the NDE1 paralogue NDEL1 has no such effects. However, NDEL1 overexpression can functionally compensate for NDE1, except at the G2-to-M transition, revealing a unique NDE1 role. In contrast, NDE1 and NDEL1 RNAi have comparable effects on postmitotic neuronal migration. - source_id: PMID:38194050 title: "Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations." statement: >- A human lissencephaly NDEL1 variant (p.R105P) that cannot bind LIS1 disrupts nucleus-centrosome coupling. supporting_text: >- Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. - source_id: DOI:10.64898/2026.06.09.730088 statement: >- Preprint: dynein inhibition (ciliobrevin D; tissue-specific dynamitin) blocks nuclear translocation of confined trunk neural crest cells in zebrafish. supporting_text: >- Using pharmacological and genetic approaches, we discover that dynein-dependent pulling forces enable nucleus translocation through confinement. - order: 3 role: perinuclear microtubule track linking the nucleus to the centrosome node: id: perinuclear_microtubule_track label: DCX-stabilized perinuclear microtubule cage module_type: BIOLOGICAL_PROCESS description: >- A centrosome-nucleated microtubule array forms a perinuclear cage whose minus ends converge on the centrosome ahead of the nucleus. The neuronal microtubule-associated protein doublecortin decorates and stabilizes these microtubules, keeping the nucleus coupled to the advancing centrosome. DCX co-immunoprecipitates with dynein in mouse neurons, possibly through LIS1; this is recorded as an association, not a direct function. concepts: - preferred_term: microtubule cytoskeleton organization term: id: GO:0000226 label: microtubule cytoskeleton organization annotons: - id: dcx_perinuclear_microtubule_stabilizer label: Doublecortin perinuclear microtubule stabilizer participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DCX (doublecortin) term: id: UniProtKB:O43602 label: Neuronal migration protein doublecortin function: preferred_term: microtubule binding term: id: GO:0008017 label: microtubule binding locations: - preferred_term: perinuclear region of cytoplasm term: id: GO:0048471 label: perinuclear region of cytoplasm role_description: >- Binds and stabilizes the microtubules running from the perinuclear cage to the centrosome; its overexpression rescues the nucleus-centrosome coupling defect of Lis1+/- neurons. evidence: - source_id: PMID:15173193 supporting_text: >- Dcx outlined microtubules extending from the perinuclear "cage" to the centrosome. - source_id: PMID:15173193 supporting_text: >- These N-C coupling defects were rescued by Dcx overexpression, and Dcx was found to complex with dynein. evidence: - source_id: DOI:10.64898/2026.06.09.730088 statement: >- Preprint: in confined neural crest cells the microtubule array reorganizes into a centrosome-associated bundle ahead of the nucleus that pulls on it (shown by laser ablation), a non-neuronal instance of the centrosome-anchored track. DCX is neuron-specific and was not examined. supporting_text: >- Under confinement, tNC cells reorganize their microtubules from a perinuclear meshwork into a polarized, centrosome-associated bundle positioned ahead of the nucleus. - order: 4 role: actomyosin contraction at the rear of the soma assisting forward nuclear movement optional: true node: id: rear_actomyosin_contraction label: Rear actomyosin contraction module_type: BIOLOGICAL_PROCESS description: >- Non-muscle myosin II accumulates behind the nucleus and its contraction pushes or squeezes the nucleus forward. Its contribution is cell-type dependent: it is prominent in tangentially migrating MGE interneurons and in zebrafish retinal interkinetic nuclear migration, and assists dynein in radially migrating cortical neurons; in cerebellar granule neurons myosin II in the leading process has also been proposed to pull the centrosome and soma forward. By contrast, dynein-driven nucleokinesis of confined trunk neural crest cells proceeds without Rho/ROCK/myosin II contractility (preprint evidence), consistent with this part being optional. Which paralog supplies the force is not resolved: the neuronal evidence comes mostly from inhibitors (blebbistatin) that block all non-muscle myosin II paralogs. MYH10 (IIB) carries neuron-migration evidence from mouse mutants. MYH9 (IIA)-specific nucleokinesis evidence comes from migrating dendritic cells rather than neurons. annotons: - id: nonmuscle_myosin_ii_contraction label: Non-muscle myosin II rear contraction participant: selector_type: FAMILY family: preferred_term: non-muscle myosin II heavy chains term: id: PANTHER:PTHR45615 label: MYOSIN HEAVY CHAIN, NON-MUSCLE representative_members: - preferred_term: MYH10 (non-muscle myosin IIB) term: id: UniProtKB:P35580 label: Myosin-10 - preferred_term: MYH9 (non-muscle myosin IIA) term: id: UniProtKB:P35579 label: Myosin-9 function: preferred_term: microfilament motor activity term: id: GO:0000146 label: microfilament motor activity role_description: >- Actomyosin contraction at the cell rear; pharmacological myosin II inhibition (blebbistatin) blocks forward nuclear translocation. The representative members are listed without implying which paralog acts in a given neuron. evidence: - source_id: PMID:15958735 title: "Nucleokinesis in tangentially migrating neurons comprises two alternating phases: forward migration of the Golgi/centrosome associated with centrosome splitting and myosin contraction at the rear." supporting_text: >- Because myosin II accumulates at the rear of migrating MGE cells, actomyosin contraction likely plays a prominent role to drive forward translocations of the nucleus toward the centrosome. - source_id: PMID:16174753 title: "Cytoskeletal coordination during neuronal migration." supporting_text: >- Time-lapse imaging and pharmacological perturbation suggest that nucleokinesis requires stepwise or hierarchical interactions between microtubules, myosin II, and cell adhesion. - source_id: PMID:19766571 title: "Actomyosin is the main driver of interkinetic nuclear migration in the retina." supporting_text: >- We also show that IKNM is driven largely by actomyosin-dependent forces as it still occurs when the microtubule cytoskeleton is compromised but is blocked when MyosinII activity is inhibited. - source_id: PMID:19607793 title: "Myosin II motors and F-actin dynamics drive the coordinated movement of the centrosome and soma during CNS glial-guided neuronal migration." supporting_text: >- Inhibition of Myosin II decreased the speed of centrosome and somal movement, whereas Myosin II activation increased coordinated movement. - source_id: DOI:10.64898/2026.06.09.730088 statement: >- Counter-example (preprint): confined neural crest nucleokinesis does not require ROCK/myosin II. supporting_text: >- Strikingly, this process occurs independently of Rho/ROCK/myosin II–mediated contractility - order: 5 role: plus-end-directed (basal) nuclear transport in interkinetic nuclear migration optional: true node: id: basal_kinesin_nuclear_transport label: Kinesin-3 basal nuclear transport module_type: BIOLOGICAL_PROCESS description: >- In radial glial progenitors the microtubules are uniformly oriented with minus ends at the ventricular surface, so basal (G1) nuclear movement requires a plus-end-directed motor. The kinesin-3 KIF1A drives this movement, providing the opposite stroke to dynein-driven apical (G2) migration. concepts: - preferred_term: interkinetic nuclear migration term: id: GO:0022027 label: interkinetic nuclear migration annotons: - id: kif1a_basal_nuclear_motor label: KIF1A plus-end nuclear motor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KIF1A term: id: UniProtKB:Q12756 label: Kinesin-like protein KIF1A function: preferred_term: plus-end-directed microtubule motor activity term: id: GO:0008574 label: plus-end-directed microtubule motor activity processes: - preferred_term: interkinetic nuclear migration term: id: GO:0022027 label: interkinetic nuclear migration evidence: - source_id: PMID:21037580 supporting_text: >- An RNAi screen of kinesin genes identified Kif1a, a member of the kinesin-3 family, as the motor for basally directed nuclear movement. - order: 6 role: CDK5/p35 phosphorylation of NDEL1 linking migration signaling to the dynein machinery optional: true node: id: cdk5_nudel_regulation label: CDK5/p35 regulation of NDEL1 module_type: REGULATORY_STEP description: >- The neuron-specific kinase complex CDK5/p35, itself essential for neuronal migration, phosphorylates NDEL1 and so modulates the LIS1-NDEL1-dynein machinery in postmitotic neurons; NDE1 is also a CDK5 substrate relevant to neuronal lamination. This is distinct from the CDK1 regulation that times nuclear-pore dynein recruitment in G2 progenitors (see the nuclear-pore route). The mechanistic consequence of NDEL1/NDE1 phosphorylation for dynein force production is not settled, so the sign of the regulation is not asserted here. annotons: - id: cdk5_p35_kinase label: CDK5/p35 kinase participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: CDK5-p35 kinase complex active_units: - id: cdk5_unit label: CDK5 catalytic subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CDK5 term: id: UniProtKB:Q00535 label: Cyclin-dependent kinase 5 role: catalytic subunit function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity - id: p35_unit label: p35 (CDK5R1) activator participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CDK5R1 (p35) term: id: UniProtKB:Q15078 label: Cyclin-dependent kinase 5 activator 1 role: kinase activator subunit function: preferred_term: cyclin-dependent protein serine/threonine kinase activator activity term: id: GO:0061575 label: cyclin-dependent protein serine/threonine kinase activator activity function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: NDEL1 evidence: - source_id: PMID:11163260 title: "NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein." supporting_text: >- Furthermore, NUDEL is a substrate of Cdk5, a kinase known to be critical during neuronal migration. - source_id: PMID:11163259 supporting_text: >- NUDEL is phosphorylated by Cdk5/p35, a complex essential for neuronal migration. - source_id: PMID:39167527 supporting_text: >- We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits Cdk5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. connections: - source: nuclear_envelope_motor_coupling target: dynein_lis1_nude_motor connection_type: PROVIDES_INPUT_FOR description: >- Envelope anchors (nesprin-2, BICD2, CENPF-NDE1/NDEL1) attach dynein to the nucleus, so that minus-end motility is converted into nuclear translocation. - source: perinuclear_microtubule_track target: dynein_lis1_nude_motor connection_type: PROVIDES_INPUT_FOR description: >- The DCX-stabilized, centrosome-anchored microtubule cage is the track along which dynein pulls the nucleus. - source: nuclear_envelope_motor_coupling target: basal_kinesin_nuclear_transport connection_type: PROVIDES_INPUT_FOR description: >- Basal movement also requires the motor to be attached to the nucleus. Nesprin-2 binds kinesin as well as dynein, but whether KIF1A itself is anchored through the LINC complex has not been established. - source: cdk5_nudel_regulation target: dynein_lis1_nude_motor description: >- CDK5/p35 phosphorylates NDEL1 within the LIS1-NDEL1-dynein module; direction of effect not asserted.