Nucleokinesis (motor-driven nuclear translocation) module

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.

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/<ORG>/ (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/<GENE>/). 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.