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• W2055873358 abstract "Regulation of nuclear movement is a critical event in neurogenesis and neuronal migration during brain development. In this issue of Neuron, Zhang et al. identify a role for SUN and the KASH-domain-containing nuclear membrane proteins as the long-sought linker between microtubules and the nucleus during brain development. Regulation of nuclear movement is a critical event in neurogenesis and neuronal migration during brain development. In this issue of Neuron, Zhang et al. identify a role for SUN and the KASH-domain-containing nuclear membrane proteins as the long-sought linker between microtubules and the nucleus during brain development. During cortical development, radial glial progenitors divide asymmetrically in the ventricular zone to replicate progenitors and generate daughter neurons. These daughters migrate along their progenitor glial fiber toward the pial surface in two sequential steps: extension of the leading process in the direction of movement, followed by abrupt movement of the cell body and nucleus, a process termed nucleokinesis (Figure 1A). In radially migrating cortical neurons, the centrosome (microtubule organizing center) precedes the nucleus as it travels up the leading process. Nucleokinesis was initially revealed from the study of the genes involved in the human brain disorder lissencephaly, displaying severe cortical lamination defects (see review by Tsai and Gleeson, 2005Tsai L.H. Gleeson J.G. Neuron. 2005; 46: 383-388Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). Mutation in LIS1, doublecortin (DCX), or tubulin alpha 1A (TUBA1A) results in human lissencephaly. LIS1 and its binding protein, NUDEL (NDEL1), are regulators of the microtubule minus-end-directed motor cytoplasmic dynein. Disruption of Lis1 (Pafah1b1), Nudel, or cytoplasmic dynein in mouse cortical neurons leads to alterations in nuclear-centrosome coupling and failed neuronal migration. DCX is a microtubule-associated protein and localizes to a perinuclear microtubule “cage” or “fork” structure and may be involved in its stabilization. The DCX-microtubule interaction is regulated by phosphorylation by the serine-threonine kinase, cyclin-dependent kinase 5 (Cdk5), which also phosphorylates many of the cytoskeletal proteins at the “cage,” including focal adhesion kinase and NUDEL. Perturbing the polarity protein Par6α, which localizes at the centrosome in migrating neurons, also results in cytoskeletal disruption and inhibits centrosomal movement. Together these studies suggested that a perinuclear microtubule “cage” structure is adjacent to the nuclear membrane and that forces exerted on this cage through the dynein motor complex associated with the nucleus generate movement toward the centrosome during nucleokinesis. As in migration, nucleokinesis is also critical for neurogenesis. The nuclei of dividing radial glia translocate basally during G1, undergo S phase at a basal location, and return to the apical surface during G2 for the subsequent M phase, a process termed interkinetic nuclear migration (INM) (Figure 1B). Recent studies showed that LIS1, dynactin, centrosomal proteins Cep120, and transforming acidic coiled-coil proteins (TACCs) are required for INM, providing a role of microtubules and dynein-dynactin complexes in this event (Gambello et al., 2003Gambello M.J. Darling D.L. Yingling J. Tanaka T. Gleeson J.G. Wynshaw-Boris A. J. Neurosci. 2003; 23: 1719-1729Crossref PubMed Google Scholar, Xie et al., 2007Xie Z. Moy L.Y. Sanada K. Zhou Y. Buchman J.J. Tsai L.H. Neuron. 2007; 56: 79-93Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, Del Bene et al., 2008Del Bene F. Wehman A.M. Link B.A. Baier H. Cell. 2008; 134: 1055-1065Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). During INM, the centrosome is localized apically, and thus the apical movement, even though in the direction opposite that of neuronal migration, is conceived to be a centrosome-directed dynein-microtubule-mediated process. All of these nucleokinesis models are built on the hypothesis that the pulling force by the dynein motor is transferred to the nuclear membrane, but it remained unknown how dynein motors were anchored to the surface of the nucleus. Clues started to emerge from the Han lab in 1999 and 2001, with the identification of the C. elegans UNC-83/UNC-84 complex at the nuclear membrane regulating nuclear migration (Malone et al., 1999Malone C.J. Fixsen W.D. Horvitz H.R. Han M. Development. 1999; 126: 3171-3181Crossref PubMed Google Scholar, Starr et al., 2001Starr D.A. Hermann G.J. Malone C.J. Fixsen W. Priess J.R. Horvitz H.R. Han M. Development. 2001; 128: 5039-5050Crossref PubMed Google Scholar). UNC-84 is a transmembrane protein with a conserved Sad1p/UNC-84 (SUN) domain at the C terminus, and localizes to the inner nuclear membrane. UNC-83 contains a conserved Klarsicht/ANC-1/Syne homology (KASH) domain consisting of a transmembrane domain followed by C-terminal 16 residues, localized to the outer nuclear membrane. Mammalian Syne-1/Nesprin-1 and Syne-2/Nesprin-2 are giant proteins (∼8797 and ∼6907 amino acids, respectively), and each contains a large N-terminal domain and a conserved C-terminal KASH domain that interact with SUN1 and SUN2. Importantly, the SUN domain interacts with the KASH domain between the inner and outer nuclear membranes in all species examined to date. Equally important is the finding that SUN proteins interact with nuclear lamins and disruption in this SUN-KASH complex results in nuclear positioning defects in diverse contexts in mammalian systems (Grady et al., 2005Grady R.M. Starr D.A. Ackerman G.L. Sanes J.R. Han H. Proc. Natl. Acad. Sci. USA. 2005; 102: 4359-4364Crossref PubMed Scopus (150) Google Scholar, Zhang et al., 2007Zhang X. Xu R. Zhu B. Yang X. Ding X. Duan S. Xu T. Zhuang Y. Han M. Development. 2007; 134: 901-908Crossref PubMed Scopus (192) Google Scholar, Lei et al., 2009Lei K. Zhang X. Ding X. Guo X. Chen M. Zhu B. Xu T. Zhuang Y. Xu R. Han M. Proc. Natl. Acad. Sci. USA. 2009; 106: 10207-10212Crossref PubMed Scopus (166) Google Scholar). Zhang et al. now show that mammalian SUN-domain proteins SUN1/2 and KASH-domain proteins Syne-1/2 are involved in nuclear-centrosome coupling during cortical neuronal migration and INM during neurogenesis (Zhang et al., 2009Zhang X. Lei K. Yuan X. Wu X. Zhuang Y. Xu T. Xu R. Han M. Neuron. 2009; 64 (this issue): 173-187Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar [this issue of Neuron]). Although Sun1 and Sun2 null mice exhibit no significant brain abnormalities, Sun1/2 double knockouts exhibit smaller brains with severe lamination defects involving the cerebral cortex, hippocampus, cerebellum, and olfactory bulb, suggesting that Sun1 and Sun2 have redundant roles in brain development. Cortical layering in double-knockout mice showed an inverted pattern, similar to mice with Reelin- or Cdk5-pathway mutations. BrdU birthdating analysis and EYFP labeling by in utero electroporation additionally showed radial migration defects. Complementing this finding is the observation that Syne-1/2 double mutants also showed identical lamination defects; however, unlike the case of Sun1 and Sun2, Syne-2 alone is essential for neuronal migration in cerebral cortex and hippocampus, but redundant with Syne-1 in other brain regions. Syne-1 and Syne-2 showed different subcellular localizations in the cerebral cortex and hippocampus; Syne-2, SUN1, and SUN2 colocalized with laminin B at the nuclear envelope, while Syne-1 showed LIS1-associated distribution around the centrosome. Syne-2 localization is disturbed in Sun1/2 double-knockout mice, suggesting that SUN proteins are required for anchoring Syne-2 to the nuclear envelope. To examine nucleokinesis in Sun1/2 double-knockout or Syne-2 mutant neurons, they used Cherry-centrin2 and EGFP-histone1B to observe dynamic coupling of centrosomes and nuclei. They found that centrosomes could migrate into leading processes but that nuclei failed to catch up to the centrosomes, exactly what one would expect for genes involved in nuclear-centrosome coupling. Because mutants exhibited smaller brain size, the authors also examined the proliferation of neural progenitors. Using S phase labeling, they found that the number of proliferating cells started to decrease by E15 and were dramatically decreased by E17.5 in the subventricular zone and intermediate zone, suggesting the loss of intermediate progenitor cells. An M phase marker showed an increase in mispositioned mitotic cells, suggesting that INM might be disrupted. To test if the proliferation defect was due to INM disruption, time-lapse recordings of nuclear movement in the ventricular zone from the Sun1/2 double-knockout or Syne-2 mutant mice were performed. They observed impaired nuclear migration toward the apical surface in both mutant mice, supporting the idea that the same SUN/KASH complex proteins are involved in nucleokinesis during INM as well as neuronal migration. From these data, the authors propose a model in which SUN1/2 interacts with lamin B (or other lamins) and forms a complex with nuclear outer membrane protein Syne-1/2 in young neurons. This complex transmits forces of microtubule motor proteins, cytoplasmic dynein, or kinesin. In this model, dynein, localized to nuclei and moving in a minus-end direction, pulls nuclei toward the centrosome, whereas one of the kinesins, with more diffuse localization and moving in a plus-end direction, either pushes nuclei away from the centrosome or exerts forces that balance dynein (Whited et al., 2004Whited J.L. Cassell A. Brouillette M. Garrity P.A. Development. 2004; 131: 4677-4686Crossref PubMed Scopus (54) Google Scholar) (Figure 1C). The data are compelling, and yet further questions emerge. First, how are the motor activities of dynein and kinesin that interact with Syne-1/2 proteins switched on and off? During INM, the stage of the cell cycle may have influence over the attachment of these motors to Syne-1 and Syne-2 or may influence motor processivity. During nucleokinesis, dynein activity is probably highly regulated, based upon the extreme saltatory nature of nuclear movements. Whether Syne-1/2 exerts influence over the motors at this stage remains an active question. Second, the large N-terminal domains of Syne-1/2 proteins may have other binding partners that can provide further levels of regulation and other functions. Interestingly, homozygous deleterious mutations in Syne-1 are thought to account for a substantial fraction of adult-onset autosomal-recessive spinocerebellar ataxia with cerebellar atrophy (SCA type 8). Heterozygous mutations in Syne-2 are identified in patients with Emery-Dreifuss muscular dystrophy (EDMD5), and Syne proteins anchor muscle nuclei at the neuromuscular junction (Grady et al., 2005Grady R.M. Starr D.A. Ackerman G.L. Sanes J.R. Han H. Proc. Natl. Acad. Sci. USA. 2005; 102: 4359-4364Crossref PubMed Scopus (150) Google Scholar). However, neither group of patients is reported to have any brain defects, highlighting important effects outside of the brain. Syne-1/2 contain calponin homology domains and spectrin repeats, involved in actin binding, as well as coiled-coil and leucine zipper domains, involved in protein-protein interactions. Additionally, they potentially undergo posttranslational modification, such as phosphorylation at multiple regions, and thus there are many points of regulation. Interestingly, the actin-myosin system component myosin II is thought to mediate contraction of the actin cortex in neuronal migration (Schaar and McConnell, 2005Schaar B.T. McConnell S.K. Proc. Natl. Acad. Sci. USA. 2005; 102: 13652-13657Crossref PubMed Scopus (251) Google Scholar, Solecki et al., 2009Solecki D.J. Trivedi N. Govek E.E. Kerekes R.A. Gleason S.S. Hatten M.E. Neuron. 2009; 63: 63-80Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar) and INM (Schenk et al., 2009Schenk J. Wilsch-Brauninger M. Calegari F. Huttner W.B. Proc. Natl. Acad. Sci. USA. 2009; 106: 16487-16492Crossref PubMed Scopus (112) Google Scholar). An obvious point of integration of these forces could be the Syne-1/2 complex. Third, are the SUN-KASH proteins only involved in radial migration? Because the phenotype observed between Sun1/2 double-knockout and Syne-1/2 double mutant mice showed disruption in neurons migrating along radial glial fibers, but not in tangentially migrating calbindin-positive interneurons, the authors suggest that SUN1/2 and Syne-1/2 proteins are specifically involved in radial neuronal migration. Although further study is required, it is possible that different sets of SUN-KASH proteins could be used during tangential migration. Finally, what might be the purpose of Syne-2 interacting with both plus- and minus-end-directed motors in INM? In Drosophila, the photoreceptor nuclear mispositioning observed in dynactin subunit, Glued, mutants was reduced in severity by reduction in kinesin heavy chain (khc) dosage (Whited et al., 2004Whited J.L. Cassell A. Brouillette M. Garrity P.A. Development. 2004; 131: 4677-4686Crossref PubMed Scopus (54) Google Scholar). Thus, it is possible that the maintenance of nuclear migration depends on a balance of plus-end and minus-end-directed microtubule motor function. Consistent with this idea, dynactin-deficient zebrafish mikre oko mutants have retinal defects in INM, where mutant progenitor nuclei migrate to the basal surface further and faster while moving more slowly in the apical direction than wild-type (Del Bene et al., 2008Del Bene F. Wehman A.M. Link B.A. Baier H. Cell. 2008; 134: 1055-1065Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar), suggesting that dynactin is involved in both apical to basal and basal to apical nuclear migration and balanced by some opposing force such as kinesin. Zhang's identification of the nuclear linker in cortical neucleokinesis and INM now makes it possible to address some of these fascinating questions. SUN1/2 and Syne/Nesprin-1/2 Complexes Connect Centrosome to the Nucleus during Neurogenesis and Neuronal Migration in MiceZhang et al.NeuronOctober 29, 2009In BriefNuclear movement is critical during neurogenesis and neuronal migration, which are fundamental for mammalian brain development. Although dynein, Lis1, and other cytoplasmic proteins are known for their roles in connecting microtubules to the nucleus during interkinetic nuclear migration (INM) and nucleokinesis, the factors connecting dynein/Lis1 to the nuclear envelope (NE) remain to be determined. We report here that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. Full-Text PDF Open Archive" @default.
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• W2055873358 date "2009-10-01" @default.
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• W2055873358 title "Sun Proteins Enlighten Nuclear Movement in Development" @default.
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