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Review
. 2010:26:421-44.
doi: 10.1146/annurev-cellbio-100109-104037.

Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges

Affiliations
Review

Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges

Daniel A Starr et al. Annu Rev Cell Dev Biol. 2010.

Abstract

The nuclear envelope links the cytoskeleton to structural components of the nucleus. It functions to coordinate nuclear migration and anchorage, organize chromatin, and aid meiotic chromosome pairing. Forces generated by the cytoskeleton are transferred across the nuclear envelope to the nuclear lamina through a nuclear-envelope bridge consisting of SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1 and Syne/Nesprin homology) proteins. Some KASH-SUN combinations connect microtubules, centrosomes, actin filaments, or intermediate filaments to the surface of the nucleus. Other combinations are used in cell cycle control, nuclear import, or apoptosis. Interactions between the cytoskeleton and the nucleus also affect global cytoskeleton organization. SUN and KASH proteins were identified through genetic screens for mispositioned nuclei in model organisms. Knockouts of SUN or KASH proteins disrupt neurological and muscular development in mice. Defects in SUN and KASH proteins have been linked to human diseases including muscular dystrophy, ataxia, progeria, lissencephaly, and cancer.

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Figures

Figure 1
Figure 1
Klarsicht, ANC-1, and Syne/Nesprin homology (KASH) and Sad1 and UNC-84 (SUN) proteins bridge the two membranes of the nuclear envelope. (a) A transmission electron microscopy (TEM) image and (b) a schematic representation of the nuclear envelope in an amphibian oocyte showing how the inner nuclear membrane (INM), outer nuclear membrane (ONM), and endoplasmic reticulum (ER) are contiguous. NPC, nuclear pore complex. A generic SUN and KASH protein bridge is drawn with conserved SUN (red ) and KASH (purple) domains in the perinuclear space of the nuclear envelope. TEM image reproduced with permission from J. Cell Biol. (Franke et al. 1981).
Figure 2
Figure 2
Genetic models for studying nuclear positioning. (a) Nuclear migration in hypodermal P cells during the first larval stage of Caenorhabditis elegans. Nuclei (dark blue) migrate from a lateral to a ventral position through the cytoplasm (light blue). P cells normally go on to form the vulva and neurons in the ventral cord. Mutations in unc-83 or unc-84 disrupt nuclear migration and the P cells die, resulting in egg-laying defective (Egl) and uncoordinated (Unc) animals. (b) Nuclear migration in C. elegans embryonic hypodermal cells. Right (light blue) and left (light green) hyp7 precursors align along the dorsal cord of a pre-elongation embryo (brown circle, dorsal view, anterior to the left) and intercalate to form a row of column-shaped cells spanning the dorsal midline. Nuclei (dark blue and dark green) then migrate the length of the cell from right to left (blue) or left to right (green). Mutations in unc-83 and unc-84 disrupt nuclear migration, and all nuclei end up in the dorsal cord instead of their normal, lateral positions. (c) Nuclear migration in the Drosophila eye disc. After the morphogenetic furrow passes, nuclei (dark blue) migrate from a basal position to an apical one as they develop into photoreceptors. In klarsicht or klaroid mutants, nuclei abnormally remain basal, disrupting the development of the eye, whereas centrosomes (black ovals) organize microtubules (red strands) from an apical position. (d ) Nuclear anchorage in the adult C. elegans syncytial hypodermis. Three large hypodermal syncytia, the hyp7 (light blue) syncytium and the lateral seam-cell syncytia (light green), are used to study nuclear anchorage. Normally nuclei (dark blue and dark green) are anchored and spaced evenly apart. In anc-1 or unc-84 mutant animals, nuclei are unanchored and often associate in clusters.
Figure 3
Figure 3
Functions of KASH-SUN nuclear-envelope bridges. KASH proteins are in the outer nuclear membrane (ONM). SUN protein dimers (gold circles) are located in the inner nuclear membrane (INM) with their SUN domains (red ) in the perinuclear space, where they interact with KASH domains (purple) to bridge the nuclear envelope. (a) Giant KASH proteins (blue) tether nuclei to actin filaments (green). (b) UNC-83 and Nesprin-4 (green) function as nucleus-specific cargo adaptors for microtubule motors kinesin-1 (red ) through the kinesin light chain (KLC, dark red ) and, at least for UNC-83, dynein (teal) through BicD and NudE/Lis1 complexes (pink and purple). (c) Klarsicht (Klar, green) is thought to interact with dynein for nuclear migration. (d-f ) Nucleoplasmic domains of SUN proteins interact with meiotic chromosomes (gray lines) through adaptors (gray circles) to aid in proper homolog pairing. (d ) Worm ZYG-12 (orange) interacts with a KASH-less isoform of itself and dynein to tether the centrosome to the nucleus, to position the nucleus, and to move chromosomes in meiosis. (e) Fission yeast Kms1 and 2 (blue) recruit dynein to move nuclei and telomeres in meiosis. (f) Budding yeast Csm4 (blue) links actin filaments to the nucleus to move telomeres through unknown intermediates (?). (g) Nesprin-3 interacts with intermediate filaments (gray) through plectin (blue). (h) Worm KDP-1 promotes cell-cycle progression. Dm, Drosophila melanogaster; Hs, Homo sapiens.
Figure 4
Figure 4
ANC-1 and Syne/Nesprin-1 and -2 tether nuclei to the actin cytoskeleton. (a) In wild-type adult C. elegans, large syncytial nuclei [green fluorescent protein (GFP) positive] are evenly spaced. (a′ ) In an anc-1 mutant animal, nuclei are unanchored and are pushed around by underlying tissues and frequently cluster together. (b) A mouse neuromuscular junction (NMJ) (red ) from a heterozygous control with four muscle nuclei (green) clustered underneath. (b′ ) In a Syne/Nesprin-1 KASH knockout mouse, nuclei fail to anchor underneath the NMJ. Reproduced with permission from Development (Zhang et al. 2007b). (c) A coronal section of an E18.5 heterozygous control mouse showing neuronal migration. Green cells were transfected with a GFP construct at E14.5. In that time, neurons migrated through the intermediate zone (IZ) to the cortical plate (CP). (c′ ) In an analogously prepared slice of a Syne/Nesprin-1 and -2 homozygous double KASH knockout brain, most nuclear migrations failed. Adapted with permission from Neuron (Zhang et al. 2009).
Figure 5
Figure 5
Functions of ZYG-1 and SUN-1/matefin. (a) A wild-type one-cell C. elegans embryo expressing GFP::tubulin. The male and female pronuclei (dark holes in background) have completed their migration, and both centrosomes remain closely attached to the male pronucleus. (a′ ) In a zyg-12 mutant embryo, the centrosomes fail to attach to the male pronucleus, and pronuclear migration fails. Reproduced with permission from Cell (Malone et al. 2003). (b) The midsection of a wild-type adult C. elegans syncytial gonad is shown. ZYG-12 (green) marks the nuclear envelope, and tubulin is shown in red. Nuclei are anchored at the periphery of the syncytial gonad. (b′ ) In a zyg-12(ct350) mutant, nuclei fall into the center of the syncytial gonad. Reproduced with permission from The Journal of Cell Biology (Zhou et al. 2009). (c) CED-4 (green) is recruited to the nuclear envelope (rings) in a C. elegans embryo. (c′ ) In a similarly staged sun-1/mtf-1 mutant embryo, CED-4 fails to be recruited to the nuclear envelope. Reproduced with permission from the Proceedings of the National Academy of Sciences, U.S.A. (Tzur et al. 2006).
Figure 6
Figure 6
Roles of KASH-SUN bridges in moving meiotic chromosomes. (a) Transmission electron microscopy image from a mouse spermatocyte showing a telomere (arrowheads) of a synapsed meiotic bivalent (extending up from telomere) attached to the inner nuclear membrane (INM) of the nuclear envelope (NE). Ch, chromatin. Reproduced with permission from The Proceedings of the National Academy of Sciences, U.S.A. (Schmitt et al. 2007). (b) A heterozygous control mouse spermatocyte showing telomeres (red ) of bivalents (green) attached to the nuclear envelope (purple). (b′ ) A spermatoycyte from a sterile Sun1 homozygous knockout mouse showing that telomeres fail to attach to the nuclear envelope. Reproduced with permission from Developmental Cell (Ding et al. 2007). (c) Sad1 (red in merge) localizes predominantly to the spindle pole body (89 min). During meiosis, some Sad1 leaves the spindle pole body, associates with telomeres (Telo, green in merge) on the INM (109 min), and moves the telomeres to the spindle pole body to form the bouquet formation (180 min). Reproduced with permission from Cell (Chikashige et al. 2006).

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