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provided by Elsevier - Publisher Connector Developmental Cell Review Feature

The SUN Rises on Meiotic Chromosome Dynamics

Yasushi Hiraoka1,2,* and Abby F. Dernburg3,4,* 1Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita 565-0871, Japan 2Kobe Advanced ICT Research Center, National Institute of Information and Communications Technology, 588-2 Iwaoka, Iwaoka-cho, Nishi-ku, Kobe 651-2492, Japan 3Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3220, USA 4Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA *Correspondence: [email protected] (Y.H.), [email protected] (A.F.D.) DOI 10.1016/j.devcel.2009.10.014

Recent studies in diverse eukaryotes have implicated a family of nuclear envelope proteins containing SUN domains as key components of meiotic nuclear organization and chromosome dynamics. In many cases, these transmembrane proteins are also known to contribute to centrosome or spindle pole body function in mitotically dividing cells. During meiotic prophase, the apparent role of these SUN-domain proteins, together with their partner KASH-domain proteins, is to connect chromosomes through the intact nuclear envelope to force-generating mechanisms in the cytoplasm.

A Family of SUN Proteins In this review, we use these existing names and also refer to these The SUN domain was named for homologous sequences shared genes and their orthologs in mouse and human genomes as Sun4 by Sad1 and UNC-84 proteins (Malone et al., 1999). Sad1 was and Sun5, respectively. The genome of Drosophila melanogaster originally identified as an essential component of the spindle contains two SUN-domain proteins, known as Klaroid and Gia- pole body (SPB), which organizes the mitotic spindle in the como, which play key roles in nuclear migration in the developing fission yeast Schizosaccharomyces pombe (Hagan and Yana- eye and sperm development, respectively. Arabidopsis thaliana gida, 1995). UNC-84 is a nuclear membrane protein required also appears to have two SUN-domain proteins, which we here for nuclear migration and positioning in the nematode Caeno- call SUN1 and SUN2. No obvious homologs had been found in rhabditis elegans, mutations in which produce an ‘‘uncoordi- the budding yeast Saccharomyces cerevisiae until Jaspersen nated’’ phenotype due to neurological defects (Malone et al., and colleagues identified Mps3 as a SUN-domain protein (Jas- 1999). The C. elegans genome contains another gene identified persen et al., 2006). Mps3 (also called Nep98) is essential for initially by its homology to unc-84, called sun-1 or matefin/mtf- mitosis. It localizes prominently to the SPB, which is embedded 1 (from the Hebrew word for ‘‘envelope’’; Fridkin et al., 2004; in the NE, and can be more faintly detected along the NE, where Malone et al., 2003). Both Sad1 and SUN-1 play major roles in it anchors telomeres and sites of DNA breaks and suppresses meiotic chromosome dynamics, in addition to their essential their recombination and repair, respectively (Antoniacci et al., roles in mitotically dividing cells, as discussed below. 2007; Bupp et al., 2007; Jaspersen et al., 2002; Nishikawa Evolutionary analysis has indicated that proteins containing et al., 2003; Oza et al., 2009; Schober et al., 2009). Like Sad1 in SUN domains are among the most broadly conserved nuclear S. pombe, this SPB protein is conscripted for a role in chromo- envelope (NE) proteins and are therefore likely to be among the some dynamics during meiosis, although the details are different most ancient in origin (Mans et al., 2004). The eukaryotic SUN- between budding and fission yeast, as described below. domain proteins are highly diverse (Jaspersen et al., 2006; Mans et al., 2004; Figure 1). Most members contain a single Mechanical Linkers of the Nucleus to the Cytoskeleton C-terminal SUN domain, but other architectures, including dupli- SUN-domain proteins are thought to be restricted to the inner cation of the domain, are also found. Figure 1A shows the archi- membrane layer of the NE. They do not have obvious nuclear tecture of those proteins containing a single C-terminal SUN localization signals, so it seems most likely that this compart- domain and at least one predicted transmembrane domain. mentalization is determined by their interaction with components Molecular phylogeny and sequence alignment of their SUN in the nucleoplasm. It is thought that their N-terminal regions domains are shown in Figure 1B and Figure S1 (available online). reside on the nuclear face of the inner nuclear membrane (INM) The nomenclature used for these proteins has not been and mediate such interactions. In some cases, these nucleo- systematic, even in cases where the orthologous relationships plasmic domains interact with nuclear lamin proteins, which are clear. In mammals, at least five genes encoding SUN-domain form a filamentous meshwork, or lamina, underlying the INM (Ha- proteins can be identified, and multiple isoforms of their tran- que et al., 2006). However, SUN-domain proteins are more wide- scripts have been documented. Three of these genes in mice spread than lamins; for example, they are apparently ubiquitous have been previously named Sun1, Sun2 (Malone et al., 1999), in fungi, which lack lamins (Mans et al., 2004). Furthermore, and Sun3 (Crisp et al., 2006), but their human orthologs are SUN-domain protein can retain localization to the NE when their known as Unc84A, Unc84B, and SUNC1, respectively. Two lamin interactions are disrupted (Hasan et al., 2006). Together, other SUN-domain genes were originally designated as rat these observations indicate that the nuclear anchors for SUN- sperm-associated antigen 4 (SPAG4) and SPAG4-like (SPAG4L). domain proteins must include components other than lamins.

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Figure 1. The SUN-Domain Protein Family (A) Primary structure of 18 SUN-domain proteins in S. pombe (Sp), C. elegans (Ce), human (Hs), mouse (Mm), D. melanogaster (Dm), A. thaliana (At), and S. cer- evisiae (Sc). UniProt protein ID: SpSad1, Q09825; CeUNC-84, Q20745; CeSUN-1, Q20924; HsSUN1, O94901; HsSUN2, Q9UH99; MmSUN1, Q6B4H0; MmSUN2, Q6B4H2; HsSUN3, Q8TAQ9; HsSUN4, Q9NPE6; HsSUN5, Q8TC36; MmSUN3, Q5SS91; MmSUN4, Q9JJF2; MmSUN5, Q9DA32; Klaroid, A1Z6Q1; Giacomo, A5HL83. International Nucleotide Sequence Databases accession number: AtSUN1, BX830640; AtSUN2, BX822923; ScMps3, DQ331910. SUN domains are indicated by green boxes. The number at the right of each bar indicates the total number of amino acid residues. Transmembrane sequences (TMs, magenta) were predicted by http://www.cbs.dtu.dk/services/TMHMM-2.0/; when obvious TMs were not predicted by this program, hydro- phobic stretches were indicated by a method of Kyte and Doolittle (1982) in GENETYX-MAC (pinkish gray in CeSUN-1 and Klaroid). (B) An unrooted phylogenic tree of the 18 SUN domains generated by a nearest junction method in ClustalW. Members whose functions in meiosis have been demonstrated are shown in red. Meiotic functions have no obvious relationship with phylogeny.

The C-terminal SUN domain (or domains) resides within the has emerged to indicate that KASH-domain proteins are lumenal space between the inner and outer nuclear membranes, glycosylated. as indicated by immunoelectron microscopy (Hodzic et al., The N-terminal regions of KASH-domain proteins are highly 2004). In animals, evidence indicates that the SUN domain variable and often enormous and are thought to protrude into mediates interactions with transmembrane proteins containing the cytoplasm. They typically contain cytoskeletal linker motifs a weakly conserved motif termed the KASH domain, for the such as spectrin repeats or HOOK domains. Genetic and prototypical Klarsicht (Drosophila), ANC-1 (C. elegans), and biochemical studies have indicated that these proteins interact Syne (mammals) homology (Apel et al., 2000; Mosley-Bishop with various cytoskeletal structures (reviewed in Starr and et al., 1999; Starr and Fischer, 2005; Starr and Han, 2002). Fischer, 2005; Tzur et al., 2006; Wilhelmsen et al., 2006). The The KASH domain is a short (30 aa) C-terminal motif that lies emergent view is that SUN-domain and KASH-domain proteins adjacent to a transmembrane domain. The localization of spanning the NE can link structures within the nucleus, such as some KASH-domain-containing proteins to the NE has been the lamina and/or the chromosomes, to cytoskeletal compo- shown to depend on their physical interaction with SUN- nents. Although SUN-KASH pairs were originally identified domain proteins, and this attribute may be shared by all family based on roles in nuclear migration and positioning (reviewed members. Fungal proteins that interact with SUN-domain in Starr and Fischer, 2005; Tzur et al., 2006; Wilhelmsen et al., proteins, including fission yeast Kms1 and budding yeast 2006; Burke and Roux, 2009 [this issue of Developmental Csm4, lack recognizable KASH domains and may therefore Cell]), it is becoming clear that they contribute to other functions, carry an analogous motif that can interact with the SUN domain; particularly chromosome organization and dynamics. we will refer to these here as KASH-domain proteins for sim- plicity. Computational analysis indicates that the SUN domain Partner Switching among SUN- and KASH-Domain is derived from a carbohydrate-binding motif known as a Proteins discoidin domain (Mans et al., 2004), suggesting that SUN During neuronal development in mice, Syne proteins, also known domains might interact with glycans. However, no evidence as nesprins, play key roles in anchoring myoblast nuclei at the

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neuromuscular junction (Zhang et al., 2007). Recent work has on their contributions to mitotic SPB function: Sad1, a founding shown that two SUN-domain proteins, Sun1 and Sun2, play member of the SUN family, and Kms1, which interacts with Sad1 partially redundant roles in this anchoring mechanism (Lei and contains a C-terminal region resembling a KASH domain et al., 2009), suggesting that nesprins may be able to interact (Chikashige et al., 2006; Starr and Fischer, 2005). Upon cells’ with multiple partners. However, how the SUN-KASH interac- entry into meiosis, Sad1-Kms1 complexes, which normally tions might be regulated is currently unknown. localize exclusively at the SPB (Miki et al., 2004), relocalize In C. elegans, the SUN-domain protein UNC-84 is required for with telomeres at dispersed positions along the NE (Chikashige nuclear migration and positioning during development (Malone et al., 2006; Y. Chikashige and Y.H., unpublished data for et al., 1999). This function is mediated by microtubules through Kms1). Eventually, these dispersed telomeres coalesce at the interaction with the UNC-83 KASH-domain protein (McGee SPB (Chikashige et al., 2006; reviewed in Chikashige et al., et al., 2006; Starr et al., 2001). UNC-84 also interacts with at least 2007). Kms1 interacts with dynein microtubule motors in the two other KASH-domain proteins: ANC-1, which is required to cytoplasm (Goto et al., 2001; Miki et al., 2004). Notably, the anchor the nucleus to actin filaments (Starr and Han, 2002), Kms1-Sad1 complex is able to capture telomeres and tether and KDP-1, which is involved in cell-cycle progression (McGee them to the SPB in the absence of cytoplasmic dynein (Yama- et al., 2009). KDP-1 requires SUN-1 for proper localization in moto et al., 1999), but the interaction of Kms1 with dynein is the germline but also localizes to the NE in tissues where SUN- essential to drive oscillatory chromosome and nuclear motion 1 is absent, suggesting the possibility of other SUN partners. (Chikashige et al., 2007). Taken together, these findings provided SUN-1 also interacts with the KASH-domain protein ZYG-12 in the first hint that SUN-KASH proteins can act as more than just embryonic and germline nuclei, where it plays key roles in a static linker between nuclear and cytoplasmic components— centrosome attachment, nuclear positioning, and meiotic chro- they can move within nuclear membranes and establish de mosome dynamics (Malone et al., 2003; Penkner et al., 2007; novo interactions with cytoskeletal components to actively Zhou et al., 2009). These data indicate that a particular SUN choreograph chromosome dynamics (Figure 2). Interestingly, it domain can interact with multiple KASH partners (also reviewed has been demonstrated that in S. pombe, mutations that disrupt in Tzur et al., 2006). This ability to switch partners may enrich the meiotic telomere attachment to the SPB (e.g., taz1, bqt1, and versatility of SUN and KASH proteins to contribute to distinct bqt4) lead to defects not only in homologous pairing but also in functions in different cell types. meiotic spindle formation (Tomita and Cooper, 2007; Chikashige et al., 2009). This may reflect an inability of SPB components to Active Players Driving Chromosome Movements properly coalesce and to balance spindle forces if their connec- The original biological functions attributed to SUN-KASH- tion to chromosomes is disrupted during meiotic prophase. domain pairs suggested that they mediate motion of the whole nucleus by interacting with dynamic cytoskeletal networks. Intranuclear Movements of Meiotic Chromosomes Consistent with that notion, mammalian Sun1 and Sun2 were in Other Organisms shown to be extremely immobile within the NE of HeLa cells As these discoveries were made in S. pombe, analogous stories (Lu et al., 2008). However, studies of meiotic nuclei have led to began to emerge from studies of meiosis in other organisms. a much more dynamic view of SUN-KASH-domain proteins. Classic cytological evidence dating from the early 1900s from Recent studies have extended the known roles for SUN-KASH widely divergent organisms revealed that chromosome ends proteins by showing that these bridges can link on the nucleo- associate with the nuclear membrane and frequently cluster, plasmic face to specific chromosomal loci to orchestrate chromo- forming a meiosis-specific arrangement called the ‘‘bouquet’’ some organization and dynamics. Such intranuclear movements (reviewed in Scherthan, 2001; Zickler and Kleckner, 1998). This of chromosomes were first documented during meiotic prophase configuration occurs during early meiosis, roughly coincident in the fission yeast S. pombe. During fission yeast meiosis, telo- with the establishment of homologous chromosome pairing meres establish interactions with the NE that lead to their clus- and synapsis. Indeed, it is a reasonable assumption that large- tering adjacent to the SPB (Chikashige et al., 1994; reviewed in scale movements must be universally important during early Hiraoka, 1998). Telomeres are also associated with the NE in meiosis, since when meiosis initiates, each chromosome is vegetative cells, but their motion becomes much more dramatic generally at some distance from its homologous partner. during meiotic prophase as a consequence of the meiosis- Large-scale movement of the entire nucleus during meiotic specific expression of at least two proteins, Bqt1 and Bqt2 (Chika- prophase has not been reported outside of S. pombe. However, shige et al., 2006). Dispersed, NE-associated telomeres first move intranuclear chromosome movement has been directly observed to cluster at the SPB, after which the entire nucleus is dragged by during meiotic prophase in other organisms, e.g., in rat sper- microtubules and associated motors back and forth along the matocytes (Parvinen and So¨ derstro¨ m, 1976) and in budding length of the conjoined cells. The SPB and associated telomere yeast (Scherthan et al., 2007; Trelles-Sticken et al., 2005). The cluster remain at the leading edge of this ‘‘horsetail’’ nucleus as extent to which such movements are driven by active, motor- it oscillates back and forth for most of meiotic prophase, which based mechanisms versus polymer diffusion is an area of active typically lasts about 2 hr. It is likely that the oscillation of the entire investigation. nucleus facilitates chromosome alignment to promote pairing of Recent discoveries in several organisms have revealed roles homologous chromosomes and at the same time agitates chro- for SUN-domain proteins in meiotic organization and movement mosomes to interrupt transient nonhomologous interactions. of chromosomes. These findings have come from studies in Meiotic telomere attachment to the SPB, clustering, and mammals, the nematode C. elegans, and the budding yeast S. motion require two proteins that were initially identified based cerevisiae. Evidence has recently emerged that these events

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Figure 2. SUN-KASH-Mediated Chromosome and Nuclear Movements (A–C) Intranuclear movement of telomeres (A and B) and movement of the entire nucleus (C) in S. pombe. (D) Enlarged view showing components connecting telomeres to microtubules. Components in other organisms are summarized in Table 1. SUN and KASH proteins form a complex in the nuclear membranes. Telomeres or pairing centers are connected to the SUN protein upon appearance of meiosis-specific chro- mosomal connectors. The KASH protein interacts with cytoskeletal networks, microtubules, or actin filaments. SUN-KASH movements are mediated by actin in S. cerevisiae, whereas they are mediated by microtubules in S. pombe and C. elegans. involve a common cast of players: NE proteins containing SUN or et al., 2007). Careful analysis of Sun1 knockout mice revealed KASH domains, meiotically expressed chromosomal connector defects in telomere-nuclear membrane attachment and homolo- proteins, and cytoskeletal proteins (Figure 2; summarized in gous chromosome pairing. Thus, although Sun1 and Sun2 Table 1). appear to have partially redundant functions in mammalian Mammals somatic cells (Lei et al., 2009), Sun1 is clearly essential for meiotic Electron microscopy of mammalian spermatocytes has shown chromosome dynamics in the mouse. that sites of chromosome attachment to the NE are marked by Although these studies of localization were carried out in fixed a densely staining structure known as an attachment plaque (Es- spermatocytes, it can be inferred that the protein moves within ponda and Gime´ nez-Martı´n, 1972; Woollam et al., 1967). Immu- the NE during meiosis, because Sun1 and/or Sun2 relocalize nolocalization of Sun1 and Sun2 from rat and mouse revealed from a diffuse distribution along the envelope to discrete foci that these proteins concentrate at sites of telomere attachment (Ding et al., 2007; Schmitt et al., 2007). We do not yet know which to the NE during meiotic prophase in spermatocytes, whereas specific cytoskeletal elements might be required for telomere they are distributed more uniformly along the NE in somatic cells movements during mammalian meiosis, although colchicine treat- (Ding et al., 2007; Schmitt et al., 2007). Immunoelectron micros- ment has been shown to disrupt homologous chromosome copy confirmed that Sun2 is associated with the attachment pla- synapsis (Tepperbergetal., 1999).Also unknown isthe mechanism que structure in rats (Schmitt et al., 2007). Sun1 was also shown by which telomeres associate with Sun1 at the nuclear periphery. by immunofluorescence to localize with telomeres during early By analogy to S. pombe,itislikelythatmeiosis-specificlinker meiosis in mouse spermatocytes. Although a function for Sun2 proteins are involved in establishing this nuclear organization. during meiosis has not yet been demonstrated, deletion of S. cerevisiae Sun1 in mice results in normal development but complete In the budding yeast S. cerevisiae, clustering of telomeres in sterility in both males and females due to meiotic failure (Ding meiosis is also observed during the pairing and recombination

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Table 1. Components Connecting Chromosomes to the Cytoskeleton S. pombe C. elegans S. cerevisiae Mouse KASH-domain protein Kms1 ZYG-12 Csm4 unidentified SUN-domain protein Sad1 SUN-1 Mps3 Sun1, Sun2 Meiosis-specific connector Bqt1, Bqt2 HIM-8, ZIM proteins Ndj1 unidentified Chromosomal loci tethered telomeres pairing centers telomeres telomeres

of homologous chromosomes (Rockmill and Roeder, 1998; recognizable KASH domains, raising the possibility that Csm4 Trelles-Sticken et al., 2000; Wu and Burgess, 2006). However, may interact directly with Mps3. Alternatively, a KASH-domain it appears that telomere attachment and clustering play a rela- protein required for telomere movement during meiosis in S. cer- tively minor role relative to what has been observed in fission evisiae may yet be discovered. yeast. Mutations that disrupt telomere attachment or movement C. elegans result in defects in the distribution of meiotic recombination During meiosis in the nematode C. elegans, telomeres do not events and low levels of chromosome nondisjunction, but the appear to play a key role in chromosome dynamics. Instead, it progression of meiosis and the ability of homologs to pair and appears that nuclear reorganization functionally analogous to the synapse are only subtly affected. In this organism, large-scale meiotic bouquet is mediated by special regions on each chromo- translocation of the entire nucleus is not observed, but contin- some known as homolog recognition regions, or pairing centers. uous deformation of the nuclear surface has been reported (Hay- These regions act in cis to promote pairing and synapsis of indi- ashi et al., 1998). Recent studies have shown that intranuclear vidual chromosomes (MacQueen et al., 2005; Villeneuve, 1994). movements of telomeres are coupled with protrusions of the The pairing center on each chromosome is bound by a single nuclear surface and that this motion is mediated through actin member of a family of four zinc-finger proteins known as HIM-8 filaments (Conrad et al., 2008; Koszul et al., 2008; Scherthan and ZIM-1, -2, and -3. Each of these proteins is essential for proper et al., 2007; Trelles-Sticken et al., 2005). meiosis, but none of them appears to play a critical role in somatic Some of these experiments have revealed the identity of the cells, at least individually. These proteins and their bound chromo- molecules that couple telomeres to the actin cytoskeleton. Ndj1 some sites interact with the NE during meiotic prophase (Phillips (also called Tam1) is a meiosis-specific protein that associates and Dernburg, 2006; Phillips et al., 2005). The sites where they with telomeres (Chua and Roeder, 1997; Conrad et al., 1997). are attached to the NE become transiently enriched for the SUN- Loss of Ndj1 causes defects in telomere clustering and homolo- and KASH-domain proteins SUN-1 and ZYG-12 during early gous recombination during meiosis (Conrad et al., 2008; Kosaka meiotic prophase (Penkner et al., 2007; Sato et al., 2009). In mitot- et al., 2008; Scherthan et al., 2007; Trelles-Sticken et al., 2000; ically dividing cells, these proteins are distributed homogenously Wanat et al., 2008; Wu and Burgess, 2006). In the absence of around the nuclear surface. They play a critical role in tethering Ndj1, telomere movements are lost, while the nuclear membrane centrosomes to the nucleus in embryos (Malone et al., 2003)and movements continue, indicating that Ndj1 connects the telo- in positioning germline nuclei (Zhou et al., 2009). The reorganiza- meres to the nuclear membranes. Mps3 is a SUN-domain protein tion of SUN-1 and ZYG-12 during meiosis implies that these that localizes to the SPB in vegetative cells (Jaspersen et al., proteins are able to move within the NE, and their dynamic 2002; Nishikawa et al., 2003). The N terminus of this protein, behavior has been directly observed through in vivo imaging thought to be its nucleoplasmic domain, was found to interact (Sato et al., 2009; Penkner et al., 2009). Differences in their directly with Ndj1 by yeast two-hybrid analysis and was subse- behavior in somatic versus meiotic cells appear to be controlled quently shown to be required for normal meiotic telomere clus- by several closely spaced phosphorylation sites within the N-ter- tering and motion (Conrad et al., 2007). During meiotic prophase, minal (nucleoplasmic) domain of SUN-1 (Penkner et al., 2009). Msp3 redistributes to multiple dynamic ‘‘patches’’ along the NE, Reduction or loss of SUN-1 or ZYG-12 results in aberrant corresponding to telomere attachment sites. Unlike in S. pombe, synapsis between nonhomologous chromosomes (Penkner these patches do not stably coalesce at the SPB, but they do et al., 2007; Sato et al., 2009). ZYG-12 interacts with cytoplasmic show a tendency to be in the same region of the membrane. dynein (Malone et al., 2003). Somewhat surprisingly, loss of dynein In addition to Ndj1, another meiosis-specific protein, Csm4, is delays but does not abrogate pairing at the pairing center regions. also necessary to connect telomeres to the NE. Loss of Csm4 Instead, loss of dynein results in failure of polymerization of the also causes defects in telomere clustering and homologous synaptonemal complex (SC), a protein structure formed between recombination during meiosis (Conrad et al., 2008; Kosaka homologous chromosomes during meiosis. Microtubule-depoly- et al., 2008; Wanat et al., 2008). In the absence of Csm4, the merizing agents, including colchicine, inhibit homolog pairing, motion of the nuclear membranes is also markedly reduced, sug- indicating that microtubules are required for pairing but that gesting that Csm4 couples force from actin cables to the nuclear dynein is required at a discrete step, to enable chromosomes membranes (Koszul et al., 2008). This suggests that Csm4 may paired at their pairing center regions to progress to synapsis. be physically associated with the outer nuclear membrane, but One interpretation of this finding is that dynein allows chromo- high-resolution localization has not yet been reported. Csm4 somes to attain more complete alignment, which in turn allows has a single transmembrane domain in its C-terminal region, the SC to polymerize. However, in sun-1 mutants, SC polymerizes but it lacks an obvious KASH motif. However, as mentioned between nonaligned chromosomes (Penkner et al., 2007), indi- above, known SUN-domain-interacting proteins in fungi lack cating that alignment is not required for SC polymerization.

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Together, these data suggest that dynein is required for a discrete mechanism linking chromosomes to cytoskeletal structures step in the process of pairing and synapsis that we have termed (Ris, 1975) that is partially preserved in both the NE-associated ‘‘licensing.’’ We envision that dynein may exert a force that SPB structure in fungi and also in more primitive protomitotic attempts to separate paired chromosomes and that the resulting chromosome segregation mechanisms. Chromosomes in most tension may be the cue that allows SC polymerization to initiate. of the familiar experimental organisms have kinetochores, a Dynein, SUN-1, and ZYG-12 were recently shown to play addi- specialized structure formed on the centromere that is captured tional roles in nuclear positioning in the C. elegans germline. by spindle microtubules to segregate chromosomes. However, Microtubules that appear to nucleate at the cell surface contact in some organisms that undergo a closed mitosis, kinetochore- the NE and interact with ZYG-12 (Zhou et al., 2009). Notably, like structures are formed at a centromere-NE attachment site, during the period in which homolog pairing and synapsis are and chromosomes are segregated by microtubules that reach taking place, the positioning of meiotic nuclei within the cells of the nucleus from outside (Oakley and Dodge, 1974; Ris, 1975). the gonad becomes less uniformly central (A.F.D., unpublished Thus, chromosome movements along the NE may reflect a data), perhaps reflecting an imbalance of forces acting at the primitive way to segregate chromosomes during mitosis. This NE as SUN-1 and ZYG-12 are conscripted to the sites of pairing similarity in proposed function between mitotic centromeres centers rather than being distributed throughout the envelope as and meiotic telomeres is intriguing in light of a recent proposal they are in earlier and later stages. that eukaryotic centromeres may be derived from telomeres (Villasante et al., 2007). The evolutionary diversity of connector Developmentally Regulated Chromosomal Connectors proteins may provide flexibility in tethering and moving different As described above, the S. pombe meiotic proteins Bqt1 and chromosomal loci, through the expression of cognate connector Bqt2 act to connect telomeres to a SUN-domain protein, Sad1, proteins, to reorganize intranuclear chromosome arrangement during telomere clustering. Sad1 is exclusively localized at the under developmental regulation. SPB but forms foci at the telomere in the presence of the connector proteins Bqt1 and Bqt2. In mice, uniform localization SUPPLEMENTAL DATA of Sun1 and Sun2 at the NE, as seen in somatic cells, is lost as these proteins accumulate at the telomeres in meiotic prophase. Supplemental Data include one figure and can be found with this article online at The de novo association of these SUN-domain proteins with telo- http://www.cell.com/developmental-cell/supplemental/S1534-5807(09)00436-5. meres during meiosis suggests the existence of meiosis-specific connector proteins or modifications to ubiquitously expressed ACKNOWLEDGMENTS proteins. To date, the proteins that act as meiosis-specific connectors between chromosomes and the NE, including Bqt1 We thank A. Sato and Y. Chikashige for helpful comments on the manuscript. We also thank D. Starr, K. Zhou, and V. Jantsch for sharing information prior to and Bqt2, Ndj1, and the ZIM/HIM-8 family, have been unique publication. to specific evolutionary lineages. 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