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First published online December 11, 2006
doi: 10.1242/10.1242/jcs.03295

Journal of Cell Science 119, 5021-5029 (2006)
Published by The Company of Biologists 2006
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KASH-domain proteins in nuclear migration, anchorage and other processes

Kevin Wilhelmsen, Mirjam Ketema, Hoa Truong and Arnoud Sonnenberg*

Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands


Figure 1
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  		Fig. 1. Phenotypes of the C. elegans mutants anc-1, unc-83, unc-84 and zyg-12. (A) In C. elegans, hyp7 precursor cells go through a series of elongation and alternating intercalation events on the dorsal side of the developing embryo. In the wild-type embryo, the nuclei (grey and black circles) then move to the opposite side of the embryo (S3). After fusion of the hyp7 precursors into the large multi-nucleated hyp7 syncytium, the nuclei are evenly anchored near the dorsal midline (DM) (S4). Unc-83 and some unc-84 mutant alleles result in failure of the nuclei to migrate past the DM (S3); these are therefore mispositioned in the syncytium, although they appear to be anchored (S4). In the anc-1 worms, the nuclei migrate normally (S3) but are unanchored and typically form clumps in the syncytium (S4). The majority of the unc-84 mutant alleles, and all the unc-83 anc-1 double mutants, result in incorrect positioning and anchorage of the nuclei in the syncytium (S4). For simplicity, only a few of the hyp7 precursor cells are depicted. (B). In the single-celled embryo of C. elegans, MTs associated with the two centrosomes pull the two pronuclei (black ovals) together; these then fuse and the nuclear envelope breaks down. At the start of the first mitosis, MTs associated with the centrosomes pull the paired chromosomes apart. In the zyg-12 worms, the centrosomes are detached from the pronuclei. As a result, the nuclei are not pulled together and do not fuse properly. The nuclear envelopes still break down and the chromosomes from each pronucleus still associate with MTs. Cytokinesis occurs but results in daughter cells that contain abnormal numbers of chromosomes.

 

Figure 2
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  		Fig. 2. Proposed protein complexes spanning the NE in C. elegans, Drosophila and mammals. The nuclear lamins of several species are proposed to interact with the N-terminal regions of the SUN-domain proteins of the INM. Within the PS, the SUN-domains (or regions immediately upstream of the SUN-domains) associate with the KASH domains of ONM proteins. Within the cytoplasm, the N-terminal regions of these proteins associate with the microtubule-organizing center (MTOC), MTs, F-actin or plectin (which can directly bind to the IFs). Thus, there is a continuous protein scaffold from the nuclear lamina, through the NE, to the different cytoskeletal systems in several different species. The SUN-domain proteins are shown as dimers. SUN1 crosses the INM three times, whereas the other SUN-domain proteins cross it at least once. The two Drosophila SUN-domain proteins identified in database searches (labeled Dm-SUN in this depiction) do not contain any recognizable membrane spanning regions, although these may not represent full-length sequences.

 

Figure 3
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  		Fig. 3. Phenotypes of the Drosophila mutants klarsicht and Msp-300SZ-75. (A) In the wild-type eye imaginal disc, passage of the morphogenetic furrow (MF) initiates the differentiation of photoreceptors. Normally, the nuclei (black circles) are pulled up to the apical side through an association with the centrosome and MTs. In the klarsicht mutant flies, the centrosomes are no longer attached to the nuclei. As a result, the nuclei remain at the basal side. (B) At the start of stage 10B in wild-type Drosophila ovaries, the nurse cells (NCs) start to dump their cytoplasmic contents into the oocyte through the ring canals. By stage 13, most NCs, and their nuclei (large black ovals), have disappeared and the dorsal appendages are extruded at the anterior end. In Msp-300SZ-75 flies, the NC nuclei become detached once cytoplasmic dumping occurs and either form multi-nucleated cells, enter the oocyte or become mispositioned within individual cells. The germinal vesicle (GV) (the oocyte nucleus) (grey oval) is also mispositioned. For simplicity, only some of the NCs are depicted. A, anterior; P, posterior.

 

Figure 4
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  		Fig. 4. Alignment of KASH domains from various proteins. The amino acid residues present in the predicted transmembrane regions are enclosed by red lines. The Zyg-12B KASH domain sequence is used because the Zyg-12C KASH domain sequence in the database lacks 16 residues encompassing part of the neck and transmembrane regions. Dark green, conserved amino acids; light green, amino acids with similar chemical properties in more than half of the KASH domains. Mm, Mus musculus; Hs, Homo sapiens.

 

Figure 5
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  		Fig. 5. In mammals, a continuous protein scaffold connects the extracellular matrix to the nuclear lamina via IFs and F-actin. Integrin {alpha}6ß4, present in hemidesmosomes (HDs), and ß1/ß3 integrins, present in focal contacts (FCs), connect the extracellular matrix (ECM) to cytoplasmic IFs (via plectin) and F-actin (via talin), respectively. These two cytoskeletal systems are interconnected to each other via the plakins (yellow circles) or to themselves via filamin or {alpha}-actinin (red circles) and the plakins (grey circles). F-actin associates with the ABDs of nesprin-1 and nesprin-2; IFs associate with plectin dimers bound to nesprin-3. In turn, the ONM nesprins associate with either SUN1 or SUN2 within the PS. The INM SUN-domain proteins associate with lamin A through their N-termini within the nucleus. ER, endoplasmic reticulum; INM, inner nuclear membrane; ONM, outer nuclear membrane; PM, plasma membrane; PS, periplasmic space.

 

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© The Company of Biologists Ltd 2006