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Positioning cytokinesis
Snezhana Oliferenko, Ting Gang Chew and Mohan K. Balasubramanian Genes Dev. 2009 23: 660-674 Access the most recent version at doi:10.1101/gad.1772009

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REVIEW

Positioning cytokinesis
Snezhana Oliferenko,2 Ting Gang Chew, and Mohan K. Balasubramanian1
Temasek Life Sciences Laboratory and the Department of Biological Sciences, National University of Singapore, Singapore 117604, Singapore

Cytokinesis is the terminal step of the cell cycle during which a mother cell divides into daughter cells. Often, the machinery of cytokinesis is positioned in such a way that daughter cells are born roughly equal in size. However, in many specialized cell types or under certain environmental conditions, the cell division machinery is placed at nonmedial positions to produce daughter cells of different sizes and in many cases of different fates. Here we review the different mechanisms that position the division machinery in prokaryotic and eukaryotic cell types. We also describe cytokinesis-positioning mechanisms that are not adequately explained by studies in model organisms and model cell types. Cytokinesis is the terminal step in the cell cycle when barriers in the form of new membranes (and cell walls in some cases) are generated, so as to divide a mother cell into two daughter cells. Studies of cytokinesis have largely focused on three major questions: (1) What is the machinery that physically divides a cell? (2) How and where in the cell is this machinery positioned? and (3) What regulates the timing of assembly of new membranes (and cell wall) such that the process of cytokinesis does not cause inadvertent damage to the genetic material? Several excellent recent reviews focus on the description of the machinery that various cell types use for cytokinesis as well as the cell cycle regulation of cytokinesis (McCollum and Gould 2001; Guertin et al. 2002; Wang 2005). In this article, we will briefly introduce the cell division machinery but will largely focus on the mechanisms of its positioning. The cytokinetic machinery In all cell types, elements of the cytoskeleton assemble into distinct supramolecular assemblies to facilitate cell division (Fig. 1). A summary of molecules participating in cytokinesis in various organisms is provided in Table 1. In animal, yeast, and fungal cells filamentous actin (F-actin), type II myosin, and several other proteins assemble into

a structure that resembles a ring or a belt in a plane perpendicular to the axis along which the chromosomes are segregated (Schroeder 1968, 1973; Fujiwara and Pollard 1976; Mabuchi and Okuno 1977; Marks et al. 1986; Balasubramanian et al. 1992; Bi et al. 1998). Constriction of this so-called actomyosin or contractile ring generates the forces necessary for the cleavage of a mother cell into two daughters. Constriction of the ring is precisely coordinated with membrane trafficking events such that the new membranes and cell walls (in fungi) are added in concert with ring constriction. In nearly all bacteria, the tubulin-like protein FtsZ assembles into a ring structure that is perpendicular to the axis of chromosome segregation (Bi and Lutkenhaus 1991). This so-called Z-ring is attached to the overlying plasma membrane via integral membrane proteins (Hale and de Boer 1997; Pichoff and Lutkenhaus 2005). Although molecular motors resembling the canonical eukaryotic microtubule-based motors, such as kinesins and dyneins, have not been discovered in bacteria, the Z-ring serves to recruit proteins important for division septum assembly. Septum assembly then ensues in coordination with constriction of the bacterial Z-ring. Although a contractile actomyosin-based apparatus has not been discovered in plants, microtubules organize into two mirrored bundles that serve to recruit machinery important for assembly of new membranes and cell wall. These dynamic microtubules interact with F-actin filaments to assemble the so-called phragmoplast, a structure essential for cytokinesis in plant cells (Gunning and Wick 1985). In contrast to cytokinesis events in bacteria, yeast, fungi, and animal cells, where membranes and cell wall material are added centripetally, new membrane assembly in plant cells occurs by a process of centrifugal expansion wherein the cell wall expands outward toward the cell cortex at the division site. Spatial regulation of cytokinesis In many cell types, prokaryotes and eukaryotes included, cytokinesis results in the formation of equally sized daughter cells. However, in many instances during development (both in single and multicellular organisms), cell division produces daughters of unequal sizes and differing fates. For example, under poor nutritional conditions, the soil bacterium Bacillus subtilis divides asymmetrically to produce a small spore, which is capable of withstanding harsher

[Keywords: Animal; bacteria; cleavage furrow; cytokinesis; plant; yeast; fungi] Corresponding authors. 1 E-MAIL mohan@tll.org.sg; FAX 65-6-872-7012. 2 E-MAIL snejana@tll.org.sg; FAX 65-6872-7007. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1772009.

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Positioning cytokinesis

Despite the diversity of division site-positioning mechanisms, it appears that in most organisms, more than one mechanism functions to ensure fidelity of division site placement. In many instances in eukaryotic cells, such fidelity is established by overlapping activatory and inhibitory mechanisms. In contrast, in prokaryotes, overlapping negative regulatory mechanisms solely participate in division site selection, and stimulatory mechanisms have not been described. We will now describe in some detail division site placement mechanisms in various organisms. Bacteria Bacteria exhibit a bewildering biodiversity; as a result, no bacterium in particular serves as a model to understand bacterial cell division in general. However, given the vast number of studies in the Gram-negative bacterium Escherichia coli and the Gram-positive bacterium B. subtilis, we focus on the mechanism of division site selection in these species. In E. coli and B. subtilis, which are cylindrical in shape, division site selection depends on two overlapping inhibitory mechanisms (Fig. 2). The Mini-cell (Min) system (de Boer et al. 1989) prevents assembly of the Z-ring at the cell ends, while the process of nucleoid occlusion prevents Z-ring assembly in the vicinity of the nucleoids (chromosomal DNA) (Goehring and Beckwith 2005). Cytokinesis has also been studied extensively in Caulobacter crescentus, where a novel protein MipZ, unrelated to the Min in sequence, plays a key role in positioning the Z-ring (Thanbichler and Shapiro 2006). In E. coli and B. subtilis, the key elements of the Min system include two components, MinC and MinD, which localize to the cell ends, where they prevent assembly of Z-rings (Marston et al. 1998; Marston and Errington 1999; Pichoff and Lutkenhaus 2001; Lutkenhaus 2007; Dajkovic et al. 2008). The spatial restriction of MinC and MinD gene products to the cell poles is achieved by two unrelated proteins, MinE in E. coli (Raskin and de Boer 1997, 1999; Fu et al. 2001; Hale et al. 2001; Shih et al. 2003) and DivIVA in B. subtilis (Edwards and Errington 1997; Edwards et al. 2000). In addition, in B. subtilis, the novel protein MinJ appears to participate in linking MinCD to DivIVA (Bramkamp et al. 2008; Patrick and Kearns 2008). MinD is an ATPase, which in its ATP-bound form binds cell membranes at the cell poles. MinD-ATP at the cell

Figure 1. Assembly of cytoskeletal proteins into cytokinetic machineries in different cell types. A contractile ring composed mainly of F-actin and myosin is used for cytokinesis in animal cells and fungi. In bacteria, a tubulin-like protein FtsZ assembles into a ring-structure at the division site. Plant cells use a microtubule-based machinery known as the phragmoplast for cell division.

environmental conditions. During such a sporulation process, B. subtilis cells ignore the medial division site typically chosen during vegetative growth, and instead assemble a Z-ring at nonmedial locations in the cell. In the budding yeast Saccharomyces cerevisiae, every cell division event results in the formation of a smaller and a larger cell, each of which inherits a different fate, with the larger cell (mother cell) capable of switching its mating type, while the smaller cell (daughter cell) is incapable of doing so. Asymmetric cell divisions are also frequently observed in metazoan cells, in which the larger and smaller daughter cells inherit different fates. Since asymmetric cell division events (at nonmedial cellular locations) increase the chances of the genetic material being damaged by the constricting cell division apparatus, such divisions are largely accompanied by mechanisms that help capture the DNA-segregating apparatuses in both prokaryotic and eukaryotic cells.

Table 1. Protein families participating in cytokinesis Actin Myosin Tubulin Kinesin Dynein

Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis Animal Yes Plant Yes Yeast Yes Bacteria Yes (MreB) Protozoa Yes
a b

Yes Yes Yes No No

Yes Yes Yes No Yes

Yes No Yes No No

Yes Yes Yes Yes (FtsZ) Yes

Yes Yes Yesa Yes Yes

Yes Yes Yes No Yes

Yes Yes Yesb No Yes

Yes No Yes No Yes

Yes No Yesb No Yes

Functions in nuclear positioning in fission yeast. Functions in mitotic spindle positioning and cytokinetic fidelity in budding yeast.

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Figure 2. Selection of the division site by two overlapping inhibitory mechanisms in cylindrical bacteria. The Min system prevents FtsZ ring assembly at the cell ends, and the nucleoid occlusion machinery prevents FtsZring assembly in the vicinity of the nucleoids.

ends recruits MinC, which prevents Z-ring assembly by its ability to bind and prevent polymerization of FtsZ (Hu et al. 1999; Pichoff and Lutkenhaus 2001; Shiomi and Margolin 2007; Dajkovic et al. 2008). The boundary of the MinCD-containing zone at the cell poles is established by MinE, a protein that has the potential to displace MinC from MinD and stimulate its ATPase activity, thereby causing the release of MinD-ADP from membranes at the cell poles (Hu and Lutkenhaus 1999, 2001; Suefuji et al. 2002; Hu et al. 2003; Lackner et al. 2003). Intriguingly, MinCD is found at only one end of the cell at any given time in E. coli. However, the E. coli Min system exhibits a fascinating oscillatory behavior both in vitro and in vivo (Raskin and de Boer 1999; Fu et al. 2001; Shih et al. 2003; Loose et al. 2008). Such oscillatory behavior in vivo leads to its association with each of the cell ends for short periods of time, which in turn prevents Z-ring assembly at both ends of the cell (Raskin and de Boer 1999; Fu et al. 2001; Shih et al. 2003). In contrast, the Min system does not display an oscillatory behavior in B. subtilis and is permanently associated with both cell poles by interaction with the coiled-coil domain-containing protein, DivIVA (Edwards and Errington 1997; Marston et al. 1998). Interestingly, although the MinCD system in B. subtilis and E. coli acts to prevent FtsZ-ring assembly, the B. subtilis proteins appear to prevent FtsZ-ring assembly only in the vicinity of the new cell poles created as a result of cell division (Gregory et al. 2008). The evolutionary benefits of an oscillatory Min system over a Min system anchored to both cell poles are not understood. Studies in B. subtilis have shown that the establishment and maintenance of the position of the division site is a continuous process. Upon transfer to poorer nutritional conditions, B. subtilis cells undergo a developmental program in which a mother cell divides asymmetrically to produce a smaller spore. Time-lapse studies of sporulating cells have shown that medially organized Z-rings, assembled during vegetative growth, unravel into spirals that eventually accumulate and organize Z-rings at both ends of the cell, although only one of these matures, and only one spore is generated (Ben-Yehuda and Losick 2002). Under conditions of sporulation, levels of MinCD

are significantly reduced (Perry and Edwards 2004), which in turn permits Z-ring assembly in the vicinity of the cell ends. Interestingly, DivIVA, which normally functions to retain MinCD at cell ends, is retained at cell ends in the absence of MinCD. In the absence of MinCD, cell polelocalized DivIVA performs a novel second function and captures the origin of chromosome replication (OriC) by localizing a novel protein RacA to the cell poles (Thomaides et al. 2001; Wu and Errington 2003; Perry and Edwards 2004), so as to allow efficient segregation of a copy of the replicated chromosome into the smaller daughter (spore) cell. Curiously, sporulating wild-type Bacillus cells, but not E. coli min-mutants, accumulate a full component of the genome into the smaller daughter cells. These observations might underscore the importance of a mechanism that captures the DNA segregation machinery in organisms that have evolved to undergo asymmetric cell divisions, even in prokaryotes (BenYehuda et al. 2003, 2005). Interestingly, C. crescentus, which divides asymmetrically, uses a DNA-binding protein, ParB, to efficiently capture origins of DNA replication to achieve proper spatial coordination of DNA segregation and cytokinesis (Bowman et al. 2008; Ebersbach et al. 2008). Although the Min system represents the primary mechanism of division site placement in many cylindrical bacteria, several studies have shown that the presence of nearby nucleoids also prevents assembly of Z-rings (Woldringh et al. 1991; Yu and Margolin 1999; Sun and Margolin 2004). Two unrelated DNA-binding proteins, SlmA (E. coli) (Bernhardt and de Boer 2005) and Noc (B. subtilis) (Wu and Errington 2004), have been shown to represent key effectors of nucleoid occlusion. Although the biochemical basis of Noc function remains unknown, SlmA appears to affect Z-ring assembly by directly interacting with FtsZ (Bernhardt and de Boer 2005). It is possible that such interactions between effectors of nucleoid occlusion and FtsZ might prevent association of FtsZ-polymers with the cell membranes over nucleoids. While current studies have provided a fairly good view of mechanisms of division site placement in cylindrical bacteria, FtsZ- and Z-rings are also used for cell division in spherical bacteria. Although fewer studies have focused on spherical bacteria, it appears that Min or Minlike systems might participate to detect slight alterations in spherical morphology (Huang and Wingreen 2004), thereby determining a long DNA segregation axis, perpendicular to which the Z-ring could be assembled. A canonical Min system has been described in Neisseria and Deinococcus (White et al. 1999; Ramirez-Arcos et al. 2001). Furthermore, Min-proteins have been shown to undergo oscillations in random orientations in spherical mutant cells of E. coli (Corbin et al. 2002). Although MinC- and MinD-like proteins have not been identified in Staphylococcus and Streptococcus, as-yet-unidentified functional homologs of the Min system might exist in these bacteria. It is therefore likely that Z-ring positioning in spherical bacteria might also be under negative regulation by Min and Min-like proteins. Although relatively

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unexplored, nucleoid occlusion might also participate in Z-ring positioning in spherical bacteria. Eukaryotic cells Division site positioning in eukaryotes utilizes diverse machinery and is established at different points in the cell cycle in different organisms. For example, the site of cell division is selected in interphase in the yeasts S. cerevisiae (in G1) and Schizosaccharomyces pombe (in G2). In contrast, the site of cell division is chosen during mitosis (in late anaphase and/or telophase) in animal cells. Finally, the site of cell division is chosen early in mitosis (in prometaphase) in plant cells. Furthermore, cell division generates daughters of equal size in some organisms and cell types, whereas in other organisms and cell types, this process generates daughters of differing sizes and fates. This diversity of cell cycle and spatial regulation has led to the evolution of several mechanisms that participate in the establishment of the site of cell division in eukaryotic cells. Mitotic apparatus-independent positioning of cytokinesis Budding yeast S. cerevisiae S. cerevisiae cells grow and divide using a process of budding. At G1/S, cells assemble cortical landmark proteins, which recruit the growth machinery composed of, among others, the Cdc42 GTPase, proteins required for the assembly of F-actin patches, and the machinery targeting secretion to this incipient site from which growth via a bud would occur. The position of the cortical landmark assembly depends on the mating type of the cells. Cells of the mating types a or a, which are typically haploid, grow by the assembly of buds at axial locations that are positioned adjacent to the site of the previous division in both the daughter cells (Fig. 3). In contrast, cells of the mating types a/a, which are typically diploid, grow by assembly of buds at bipolar locations, which are

either proximal or distal to the site of previous cell division (Fig. 3; Chant and Herskowitz 1991; Chant 1999; Casamayor and Snyder 2002). Cytokinesis and cell division are achieved by the cleavage of the neck region of budding yeast cells (Fig. 3). Interestingly, since the site of cell polarization, which is established early in the cell cycle, dictates the site of cytokinesis, the mitotic apparatus does not play any appreciable role in the positioning of the division site in this organism, but instead functions later to ensure correct positioning of daughter genomes with respect to the division site. The site of bud assembly is marked by landmark proteins such as Bud3p, Bud4p, Bud10p, and Axl1p in the case of axial budding (Chant 1999; Casamayor and Snyder 2002), and Bud8p and Bud9p in the case of bipolar budding (Fig. 4; Harkins et al. 2001). These landmark proteins help recruit the Ras-related GTPase, Rsr1p/ Bud1p (Bender and Pringle 1989). Rsr1p/Bud1p, in turn, recruits the exchange factor for the Cdc42p-GTPase, Cdc24p, leading to the localized activation of the Cdc42p (Park et al. 1997). GTP-bound Cdc42p then recruits the CRIB domain-containing proteins Gic1p and Gic2p, ultimately leading to the assembly of septins at the future cell division site (Iwase et al. 2006). Septins, in turn, serve to recruit the bud-site marker proteins to the region adjacent to the division site. Rga1p, a GTPase-activating protein for Cdc42p, localizes to the division site so as to ensure that a previously used division site is not reused for polarized growth and cell division (Tong et al. 2007). Since the cell division site is chosen early in the cell cycle, and since cells do not have a default axis to allow maximal elongation of the mitotic spindle, budding yeast cells possess a robust mechanism that captures the mitotic spindle, thereby allowing migration of one of the daughter nuclei into the bud. This spindle capture is achieved by the localization of Kar9p and a dynein, Dyn1p, to one of the spindle pole bodies and asters, causing a type V myosin-dependent movement of the SPB/aster containing Kar9p and Dyn1p into the bud (Yeh et al. 2000; Schuyler and Pellman 2001; Liakopoulos et al. 2003; Sheeman et al. 2003). Failure to orient the spindle along the motherbud axis delays activation of the Mitotic Exit Network (MEN), which is essential for cytokinesis, until proper orientation of the spindle is achieved (Fig. 5; Schuyler and Pellman 2001). The fission yeast S. pombe Cells of S. pombe are cylindrically shaped and divide by placement of an actomyosin ring and a division septum that divides a mother cell into two roughly equally sized cells. The division site placement principally depends on the position of the premitotic nucleus (Paoletti and Chang 2000). The division site in fission yeast is chosen in late G2 phase and is dynamic, in that alterations in the position of the nucleus until early mitosis cause repositioning of the cell division site as well (Daga and Chang 2005; TolicNrrelykke et al. 2005). Division site selection in fission yeast involves interplay between two physical parameters: the cylindrical cell

Figure 3. Different budding patterns in haploid and diploid S. cerevisiae. Haploid cells use Bud3p, Bud4p, Axl1p, and Axl2p as the landmarks to position the bud site at axial locations. Diploid cells select the bud site using Bud8p and Bud9p as landmarks and undergo bipolar budding either at proximal or distal locations.

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Figure 4. Positioning of the division site in the budding yeast. A zone of inhibition is established by the Cdc42p GTPase activating protein Rga1p at the previous bud site. The landmark proteins are then recruited to the presumptive bud site. These landmark proteins help to recruit a Ras-related protein, Rsr1p, which leads to the recruitment of Cdc42p GEF Cdc24p, causing local activation of Cdc42p. The activated Cdc42p then recruits the CRIB domain-containing proteins, Gic1p and Gic2p, and leads to the assembly of septins at the division site. Septins, in turn, promote actomyosin ring assembly at the division site. Rga1p then localizes to the division site to ensure that a previously used division site is not reused for polarized growth and cell division.

(Fig. 6; Sohrmann et al. 1996; Paoletti and Chang 2000). Mid1p is a membrane-associated protein related to metazoan anillins in terms of domain organization. Mid1p shuttles between the nucleus and the cell cortex, localizing to the nucleus during most of interphase and to the overlying cortex in late G2 and early mitosis (Paoletti and Chang 2000). Mid1p recruits several components of the actomyosin ring to the medial region of the cell so as to allow actomyosin ring assembly overlying the position of the interphase nucleus (Motegi et al. 2004). Mid1p is exported from the nucleus upon entry into mitosis by phosphorylation by the Polo-family protein kinase, Plo1p (Bahler et al. 1998). Consequently, plo1 mutants also are defective in division site placement (Bahler et al. 1998). The polarity factors Tea1p, Pom1p, and Tea4p, which localize to the cell ends, prevent accumulation of Mid1p at one of the cell ends (the new end, which is generated following cell division) (Celton-Morizur et al. 2006; Padte et al. 2006). How Mid1p is excluded from the other (older) end remains unknown. Cells lacking Mid1p, despite the mispositioning of the division septum, do not assemble septa at the ends of the cell (Huang et al. 2007). Interestingly, this tip occlusion of septation is also achieved via Tea1p, Tea4p, and Pom1p. It appears that Tea1p, Tea4p, and Pom1p delay septum assembly, by downregulating function of the F-BAR protein Cdc15p, until actomyosin rings misplaced in the absence of Mid1p exit the cell ends (Huang et al. 2007). It is likely that such a mechanism might contribute to the fidelity of cytokinesis in smaller cells, where the ends are nearer to the mid-cell site. The protein kinase Kin1p has also been shown to participate in division placement, although mechanistic details are presently unknown (La Carbona and Le Goff 2006). Templated cytokinesis along cellular long axis in Trypanosoma brucei The African protozoan T. brucei has a highly organized and polarized cellular structure. It contains a single Golgi body and a single mitochondrion, which are located at specific intracellular positions. Correct positioning of the division machinery is thus crucial for the faithful inheritance of a nucleus and one each of these organelles. Curiously, there is no evidence at present for the

morphology and the medially positioned nucleus (Sipiczki et al. 2000; Daga and Chang 2005; Ge et al. 2005). The anillin-related protein, Mid1p, stimulates actomyosin ring assembly at the cortex overlying the nucleus (Motegi et al. 2004), while a host of so-called tip factors simultaneously inhibit cytokinesis at cell ends (Celton-Morizur et al. 2006; Padte et al. 2006; Huang et al. 2007). The cylindrical shape of fission yeast cells is established by F-actin-dependent assembly of cell wall components. Elements of the F-actin cytoskeleton, Cdc42-GTPase, and the machinery involved in a-glucan and b-glucan synthesis, are all important for the establishment and maintenance of cylindrical cellular shape (Diaz et al. 1993; Miller and Johnson 1994; Verde et al. 1998). The cylindrical shape of the cell allows spontaneous organization of anti-parallel bundles of microtubules, with a region of overlap of minus ends in the medial region of the cell (Carazo-Salas and Nurse 2006; Daga et al. 2006; Terenna et al. 2008). Since these regions of overlap are mostly associated with the nuclear envelope, spontaneous organization of microtubules within the confines of a cylindrical shape ensures medial positioning of the nucleus (Tran et al. 2001). The positioning of the nucleus dictates the site of cell division via the PH domain-containing protein Mid1p

Figure 5. Coordination of spindle orientation and cytokinesis by the MEN in budding yeast. A GTPase-driven signaling pathway, MEN is kept inactive when the mitotic spindle is not positioned at the neck region connecting the mother and daughter cells. Once the mitotic spindle is aligned along the mother and bud axis, MEN is activated to promote mitotic exit and cytokinesis.

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other Trypanosomal species as well as in other organisms such as Leishmania major, although mechanisms underlying division site placement in these organisms are not well understood. Establishment of the division plane in plant cells Plant cells are encased by cell wall material and, unlike animal cells, are unable to migrate. Thus, proper organization of pattern and morphology of plant tissues depends largely on the precise positioning of the division plane. Improper specification of the division plane in plant cells results in missegregation of cell fate determinants and defective tissue morphology and patterning. In contrast to animal cells that use an actomyosinbased contractile ring for cytokinesis, plant cells mainly use microtubule-based structures for cell division. In addition to the mitotic spindle, two additional microtubule-based cellular structures known as the preprophase band (PPB) and phragmoplast play crucial roles in plant cytokinesis (Gunning and Wick 1985). PPB is a ring-like structure composed of microtubules and F-actin that is positioned underneath plasma membrane and circumscribes the premitotic nucleus. In contrast, the phragmoplast is a structure assembled during cytokinesis that consists of two parallel microtubule bundles separated by the expanding cell plate in the middle. In most plant cell types, an array of parallel microtubule bundles oriented perpendicular to the cells long axis is organized underlying the cell cortex during interphase (Fig. 8). This cortical microtubular array contributes in interphase to the formation of PPB, whose position corresponds to that of the future division site (Hardham and Gunning 1978; Mineyuki et al. 1999). Thus, similar to yeast cells, plant cells specify their division plane before entering mitosis. As the cell cycle proceeds, the

Figure 6. Division site selection in the fission yeast S. pombe. The division site is determined by the position of the premitotic nucleus in fission yeast through Mid1p, an anillin-related protein. Mid1p shuttles between nucleus and cell cortex during interphase. Upon entry into mitosis, Polo-related kinase Plo1p promotes the exit of Mid1p from the nucleus to specify the division zone. The cortically localized Mid1p then promotes assembly of the actomyosin ring at the division site. During cytokinesis, a tip complex prevents septum assembly at the cell ends.

existence of an actomyosin-based cytokinetic apparatus in T. brucei. In T. brucei, a single flagellum is attached to the cell body via the flagellum attachment zone (FAZ) (Kohl et al. 1999). During cell cycle progression, the old flagellum guides the growth of a new flagellum along the length of the cell body (Moreira-Leite et al. 2001). After mitosis, a cleavage furrow is formed between these flagella, and the furrow ingresses unidirectionally along the long axis, initiating at the anterior and ending at the posterior side (Kohl et al. 1999). The distal tip of the new flagellum (and its associated FAZ) promotes cytokinesis from the anterior end of the cell (Fig. 7; Vaughan and Gull 2003). T. brucei mutants that are defective in intraflagellum transport (IFT) have a shorter new flagellum and, interestingly, undergo unequal cell division (Kohl et al. 2003). Thus, the length of the flagellum of T. brucei increases by IFT and the flagellar length affect the position of cleavage furrow. Procyclic cells of T. brucei in the tsetse fly midgut undergo a few rounds of symmetrical cell division and then differentiate into an epimastigote form while migrating toward the salivary glands (Sharma et al. 2008). This differentiation process also involves an asymmetric cell division in which a long cell and a short epimastigote cell are produced. The procyclic T. brucei increases its cell body length to almost double its original length prior to the asymmetric cell division, and a short new flagellum is grown from the posterior end (Sharma et al. 2008). Ingression of the cleavage furrow from the distal tip of the short new flagellum leads to the production of two daughter cells with different cell sizes (Sharma et al. 2008). Division along the long axis is also observed in

Figure 7. Cytokinesis in the African protozoan T. brucei. T. brucei duplicates its organelles such as the nucleus and the flagellum during mitosis. After completion of mitosis, cytokinesis is initiated from the anterior end to the posterior end. The cleavage furrow ingresses unidirectionally from the distal tip of the flagellum.

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Figure 8. Establishment of the division plane in plant cells. Microtubule bundles underlying cell cortex are oriented perpendicular to the cells long axis during interphase. The microtubule array condenses, and a PPB is formed underneath plasma membrane, whose position predicts the future division site. Upon entry into mitosis, the PPB is disassembled, and F-actin is depleted from the cortical region occupied by the PPB. Landmark proteins such as TANGLED remain at the PPB to mark the division site. After mitosis, a microtubule-based structure, termed the phragmoplast, is formed and expands laterally toward the cell cortex region occupied by the PPB. Targeted vesicular trafficking and fusion at the phragmoplast lead to the assembly of cell wall at the division site.

et al. 2007). Once localized to the cortex, TANGLED persists after the PPB is disassembled and remains at the future division site in a microtubule-independent manner (Walker et al. 2007). It then guides the expanding phragmoplast to the cortical area previously occupied by PPB during cytokinesis. How TANGLED guides the phragmoplast expansion toward the PPB-marked cortex remains unclear. It has been hypothesized that TANGLED resembles vertebrate adenomatous polyposis coli (APC) proteins and might potentially interact with EB1 at the plus ends of microtubules radiating from the phragmoplast. Future studies should identify the precise mechanisms by which TANGLED and related proteins function. Nevertheless, the presence of TANGLED protein in both monocots and dicots suggests that a conserved mechanism might specify the division zone in plants. Mitotic apparatus-dependent division site positioning in animal cells Cytokinesis in animal cells is achieved by constriction of the cortex between the two sets of segregated chromosomes. Many models have been suggested over the years to explain how cortical activity could be regulated: An excellent historical overview of cytokinesis studies in 19th and 20th centuries can be found in Rappaport (1986). It was eventually established that cytokinesis is initiated by signal(s) emitted from the mitotic apparatus. When the mitotic spindle in starfish eggs was pushed or rotated, the cortical contractile ring was assembled at a new position, corresponding to that of the spindle (Rappaport and Ebstein 1965; Rappaport and Rappaport 1993). These experiments demonstrated that the cortex of the echinoderm eggs is initially capable of furrowing at any location, but the orientation and position of the spindle determine the actual division plane. Therefore, the current view is that microtubules associated with the spindle apparatus play a crucial role in controlling furrow positioning and ingression. During anaphase, the mitotic spindle in most animal cells contains a set of bundled microtubules (central spindle) and two radial arrays of astral microtubules. Each of these arrays differentially controls actomyosin cortical activity and can induce furrow formation (Fig. 9). However, they often cooperate to induce furrowing specifically between separated chromosomes. The exact contributions of these various microtubular arrays differ among cell types. Regulation by astral microtubules It appears that in cells that have large asters, the astral microtubules play an important role in the determination of the cleavage plane. It has been proposed that astral microtubules may provide inhibitory signals to the polar cortical regions, resulting in local inhibition of contractility and establishment of the gradient of cortical tension. In such a manner, the highest tension and cortical furrowing would be then restricted to cell equator (Wolpert 1960; White and Borisy 1983). These models are cumulatively known as polar relaxation models. Consistently, a complete lack of microtubules leads to the enhanced,

parallel cortical microtubular array condenses at the cell cortex overlying the premitotic nucleus. Several studies have suggested that the nuclear position determines the position of PPB and the future division site (Murata and Wada 1991; Gimenez-Abian et al. 2004). Displacement of the interphase nucleus triggers the establishment of the PPB and the division site close to the new nuclear position (Murata and Wada 1991). Upon entry into mitosis, the PPB disassembles, and F-actin is depleted from the cortical region occupied by the PPB (Cleary 1992, 1995; Liu and Palevitz 1992). It has been proposed that the loss of microtubules and F-actin from the PPB leads to the accumulation of a landmark protein to mark the future division site. After chromosome segregation, the remnants of the anaphase spindle form the phragmoplast, which then expands laterally toward the cortical area occupied by the PPB. Vesicular trafficking and fusion, targeted by microtubule bundles at the edge of phragmoplast, lead to the formation of cell plate. After completion of cytokinesis, the microtubule bundles reorient their position to reform the parallel cortical microtubular array in the two newly separated daughter cells. The question of how the PPB defines the future division plane had been a puzzle for decades. Characterization of a novel protein, TANGLED, in maize and its homolog in Arabidopsis has led to the suggestion that this protein might function as the long-sought landmark protein that marks the division plane after PPB disassembly (Smith et al. 1996; Walker et al. 2007). Maize mutants defective in TANGLED function have a misoriented division plane, as the phragmoplast is not guided toward the cortex defined by PPB (Cleary and Smith 1998). A similar but weaker phenotype has been observed in the Arabidopsis tan mutant, in which a population of root-tip cells display tilted division planes that are unable to form a cell plate perpendicular to cells long axis. Arabidopsis TANGLED is recruited by microtubules and kinesins to the cortical region occupied by the PPB during interphase (Walker

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Bonaccorsi et al. 1998; Mishima et al. 2002, 2004). Thus, if the spindle is off-center, the division is asymmetric with the mother cell giving rise to two daughters of different sizes. However, in situations in which spindles do not have asters, like in oocytes during female meiosis in the mouse (Szollosi et al. 1972), the cleavage furrow position is controlled solely by the central spindle. Transmission of the furrow positioning signals from microtubule arrays to cell cortex It appears that microtubules of the spindle apparatus control cortical contractility largely by maintaining active gradients of the small GTPase Rho through the positioning of Rho regulators on microtubules. Rho is a critical regulator of cleavage furrow induction, and its activity is required for cortex furrowing, as first shown by Mabuchi et al. (1993), Kishi et al. (1993), and Drechsel et al. (1997). Similar to its function in other actomyosindependent processes, active GTP-bound Rho induces F-actin assembly (Watanabe et al. 1997) and causes activation of myosin II function (Kimura et al. 1996) at the cell equator, thereby promoting cortical constriction. Active Rho accumulates in a narrow cortical band overlying the mitotic spindle, and spindle displacement leads to repositioning of this cortical band of active Rho (Bement et al. 2005). Activities of Rho guanine nucleotide exchange factor (GEF), ECT2, and a proposed Rho GAP (GTPase-activating protein), Cyk4, are needed to sustain Rho function in cytokinesis (for review, see Piekny et al. 2005). A traditional view is that ECT2 function is initially required for the accumulation of GTP-bound Rho at the cell equator, in order to promote furrowing while downregulation of Rho through the GAP activity induces disassembly of the cytokinetic machinery and promotes completion of cytokinesis (Minoshima et al. 2003). In this manner, it is assumed that activation of Rho and its downregulation happen sequentially, driven by cell cycle cues. Recently it was reported that the GAP activity is, in fact, required throughout cytokinesis in Xenopus embryos, even at its early stages, to form and maintain the narrow Rho activity zone at the cell equator. When the GAP was inactivated, Rho activity zones were poorly focused and exhibited unstable and often oscillatory behavior early during cytokinesis, presumably triggering cytokinesis failures (Miller and Bement 2009). Thus it appears that Rho activity zones represent not simply the zones of local activation but zones where Rho undergoes fast GTPase flux. Consistent with this notion, Aurora kinase that phosphorylates Cyk4 (which otherwise exhibits a Rac GAP activity) and triggers its conversion into a Rho GAP (Minoshima et al. 2003) produces a phosphorylation gradient that extends from the spindle midzone to the cortex immediately after anaphase onset (Fuller et al. 2008). Thus it appears that the machinery is in place to enable rapid GTPase cycles of Rho precisely at the cell equator. This might provide a part of the answer to an interesting question as to how exactly the furrowing signals are transmitted from the spindle midzone to the equatorial cortex, frequently on micrometer scale distances. Cytokinetic

Figure 9. Three models for cleavage plane positioning in animal cells. Three modes of division site positioning have been demonstrated in animal cells. After chromosome segregation, the overlapping microtubule bundles at the cell midzone known as the central spindle specify the cleavage plane. In certain cell types, astral microtubules stimulate cleavage furrow formation at the division site, whereas in some cases, astral microtubules inhibit cortical contractility at the cell ends to promote cleavage furrow formation at the division site.

although disorganized, cortical contractility (Canman et al. 2000; Paluch et al. 2005). On the other hand, classic experiments of Rappaport on shaping the sand dollar eggs into toruses suggested that it is the equatorial zone where microtubule asters converge at the cortex that determines position of the cleavage furrow (Rappaport 1961). Theories that propose that a subpopulation of mitotic asters stimulate the future furrow region, possibly through delivery of a factor that could be transported along microtubules, are known as astral stimulation models. In such models, activity of the proposed furrowing activator would be highest at the equatorial cortex, where asters from two spindle poles meet. Astral stimulation has been proposed for positioning of furrows in large cells (fertilized eggs of amphibians, birds, and fish) and in cells with several mitotic apparatuses (insects). Mathematical modeling of astral stimulation correctly predicts the positioning and occurrence of furrowing when cell shape is significantly altered before division (Devore et al. 1989). Regulation by the spindle midzone Cytokinetic positioning and furrowing also appear to be influenced by proteins residing at the spindle midzone in some cell types. The role of the spindle midzone in determining the cleavage position was first determined in the studies of unequal cell division in grasshopper neuroblasts. Unequally sized asters determined the asymmetric positioning of the spindle, but it was the cell cortex nearest the spindle midzone that received cleavage stimulus. Furthermore, furrowing required the continuous stimulation from the spindle midzone (Kawamura 1977). Many studies have shown that the central spindle together with asters are involved in the positioning of the cleavage furrow (Rappaport 1985; Cao and Wang 1996;

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regulators, such as the Aurora BIncenpSurvivin complex and the central spindlin complex consisting of the kinesin-like protein MKLP1 and Cyk4, all localize to the spindle midzone during anaphase. The Aurora kinase complex is required for central spindlin localization and function (Severson et al. 2000), but it is also possible that it may have other targets. Furthermore, control of Rho activity at the cleavage furrow is not limited to regulation by Aurora kinase. The polo-like kinase 1, Plk1, promotes recruitment of the Rho GEF, ECT2, to the central spindle, independently of Aurora B (Petronczki et al. 2007). Plk1 in mammalian cells localizes to the central spindle through its interaction with the microtubule bundler PRC1 (Neef et al. 2007), which in turn interacts with several mitotic kinesins, including MKLP1-like proteins, and is important for cytokinesis (Jiang et al. 1998; Kurasawa et al. 2004; Verni et al. 2004). Plk 1 has also been copurified with MKLP1 and has been shown to directly phosphorylate the MKLP1 (Lee et al. 1995; Liu et al. 2004). Thus it appears that an interwoven network of proteins at the spindle midzone contributes to regulating Rho activity at the future division site. It is obvious from the experiments discussed above that microtubules have been proposed to provide both stimulatory and inhibitory effects on cortical stiffness and contraction. Indeed, it appears that the mitotic apparatus is indeed capable of providing two furrow-specifying signals (Dechant and Glotzer 2003; Bringmann and Hyman 2005). How could this be achieved? An interesting view is that the key parameters positively or negatively influencing the cortical contractility are stability and possibly the configuration of microtubule arrays. While a subpopulation of dynamic astral microtubules seems to cause polar relaxation, other, more stable microtubules (which could be stable astral or central spindle microtubules) stimulate contractility at the sites where they contact the cortex (Canman et al. 2003; Chen et al. 2008; Foe and von Dassow 2008; Murthy and Wadsworth 2008). Odell and Foe recently proposed a model wherein the dynamics of the central spindlin component kinesin MKLP1 are used to provide an explanation of how the differential microtubule stability could modulate cortical contractility. In their model, most MKLP1 is sequestered by a multitude of dynamic astral microtubules and does not reach the cell cortex. Therefore, Rho activation is suppressed where density of such microtubules is high. On the other hand, MKLP could be delivered to cell cortex along a subset of stable microtubules and cause Rho activation specifically at the cell equator (Odell and Foe 2008). This interesting model can indeed explain how microtubules of the spindle apparatus are capable of delivering both stimulatory and inhibitory signals to the cortex, depending on their stability and configuration. Setting up the division site in animal cells growing in the context of a tissue and the role of mitotic spindle orientation The purpose of cytokinesis is not limited to an increase in cell number. It also shapes tissues and organisms and

allows daughter cells to adopt distinct fates. In multicellular organisms, a rather simple, symmetric cell division (when a mother cell divides into approximately equally sized daughters bearing same cellular fates) is often oriented, and such orientation is essential to sustain a specific tissue shape and function. For instance, in animal epithelium, the dividing cells remain in contact with extracellular matrix and with each other, and thereby maintain the sheet-like structure of this tissue. Cell division can also result in asymmetric segregation of factors leading daughter cells to take on different fates. Such asymmetric division is widespread in nature: Unicellular organisms such as budding yeast use it to restrict damaged and oxidized proteins to the aging mother cell (Aguilaniu et al. 2003), while in complex multicellular organisms, asymmetric division site placement sets specific cellular patterns that contribute to organism development and tissue homeostasis. As spindle orientation in animal cells sets the plane of future cell division, much work in recent years has also been dedicated to elucidating mechanisms underlying spindle orientation both in two- and three-dimensional cell cultures and in the context of a tissue (for reviews, see Ahringer 2003; Gonzalez 2007). We will discuss them only briefly. When mammalian epithelial NRK cells are grown as two-dimensional cultures, they remain nonpolarized. During division their spindles appear to be oriented along the long axis of the cell (OConnell and Wang 2000). A simple and appealing explanation is that the mitotic spindle naturally aligns with the cells long axis due to geometric constraints and that this positioning ensures that the cell divides along the short axis. However, it appears that when cells are grown on the micro-patterned substrates that provide defined contacts between cell and extracellular matrix (ECM), spindle orientation is driven not simply by cell geometry but rather by cortical marks associated with so-called retraction fibers that are left during mitotic cell rounding. Such cortical marks are rich in various cytoskeletal proteins and reflect the status of cell/ECM contacts prior to division (Thery et al. 2005, 2007). Therefore, the mitotic spindle is actively oriented with respect to cell/ ECM adhesion plane or cell shape even in cells that grow out of the tissue context and are considered nonpolarized. Contributions of cell shape and cell/ECM contacts in spindle orientation in vivo are probably not mutually exclusive (and these factors might be very well be interdependent), and both mechanisms could function depending on a physiological context. When epithelial cells are grown on permeable matrix support, they form a sheet-like cellular monolayer that exhibits many properties of true epithelium. To sustain this organization through cellular expansion, a dividing cell has to ensure that it remains in contact with surrounding cells and with the matrix throughout furrow ingression. It is therefore not surprising that most spindles in polarized MDCK cells are oriented perpendicular to the long, apicalbasal, axis of the cell, allowing cell cleavage to occur in the plane of the epithelium (Reinsch and Karsenti 1994). Similarly, in the dorsal epiblast of the

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zebrafish embryo, most spindles are oriented perpendicular to the long axis of the cell, resulting in cellular division along the long axis. Again, such alignment suggests the existence of a mechanism actively driving spindle orientation. In epithelia, adherens junctions are located at lateral cell borders near the apical surface and contain polarity determinants and microtubule-binding proteins. Junctional complexes appear to capture astral microtubules, and forces generated by dynein could rotate spindles into alignment. Therefore, adherens junctions could provide the link between cell polarity and spindle orientation (Lu et al. 2001). Mutations that disrupt spindlecortex interactions can induce abnormal divisions and contribute to hyperproliferation of daughter cells (Yamashita et al. 2003, 2007; Yamashita and Fuller 2005, 2008). In the zebrafish embryo, injection of dominantnegative Dishevelled or down-regulation of Wnt pathway components (Wnt11 and Stbm) causes randomization of division orientation, implicating noncanonical Wnt signaling pathway in controlling this process (Gong et al. 2004). Thus, the axis of division may be defined by mitotic spindle orientation that in turn is driven by cellcell signaling and apicalbasal polarity cues (see also Schlesinger et al. 1999; Schober et al. 1999; Petronczki and Knoblich 2001 and others). Cell division in animal tissues: further questions and challenges Orientation of cell division in tissues can be specifically regulated in space and time to achieve the right balance of cell expansion and cell differentiation. For instance, in mouse embryonic skin, some cells eventually start dividing perpendicular to the basement membrane, yielding two daughters, one of which remains in the plane of the initial cell layer and the other becomes a so-called suprabasal cell. The number of such cells increases as skin stratification proceeds. When divisions proceed laterally to the basement membrane, skin stratification does not occur. Again, it appears that the plane of cell division is primarily determined by spindle orientation, which requires function of the Pins homolog LGN and the inscuteable homolog mInsc. While LGN and mInsc constitute the cell polarity cues, p150glued, a subunit of dyneindynactin complex, seems to function together with the spindle pole-anchoring protein NUMA to create pulling forces that could position the spindle (Lechler and Fuchs 2005). It would be of great interest to continue investigating the processes of spindle alignment and division site positioning in mouse animal models, looking at cell division in the tissue context. Yet, results of gene deletions and other gene manipulations could be notoriously difficult to interpret because of tight feedback between planar polarity and spindle orientation. Curiously, it was observed that during cytokinesis in polarized epithelial cells of mouse gastral crypts, spindles are oriented parallel to the tissue and close to the apical surface, but furrow ingression starts from the basolateral surface and, in fact, far away from either midspindle or astral microtubules (Fig. 10; Bjerknes and Cheng. 1989;

Figure 10. Cytokinesis along the cellular long axis in polarized intestinal epithelial cells. In most cultured cell lines, the division plane is positioned perpendicular to the cells long axis. In vivo, the polarized intestinal epithelial cells, however, divide along the cells long axis.

Fleming et al. 2007). Furthermore, spindle remnants and midbodies were always seen at the apical cell borders and never at the basal or lateral borders in late telophase cells, suggesting that furrow ingression proceeds in asymmetric fashion starting at the basal side and ending at the apical surface (Das et al. 2003; Royou et al. 2004; Fleming et al. 2007). So how could the spindle apparatus direct furrow ingression? Is furrowing initiated basolaterally by unknown mechanisms and then sustained through interactions with spindle and astral microtubules? In this light, it might be useful to recall the polar relaxation model, wherein relaxation of part of the cortex allows furrow ingression to occur. It would be interesting to evaluate whether such a mechanism could function in the confines of the epithelial cell geometry. It might also be possible that other factors, such as local activation of actin depolymerization or loss of actin cytoskeleton cross-linking, could result in a similar functional outcome. For instance, it has been shown that depletion of the actin cross-linking protein a-actinin leads to a highly unstable cortex and asymmetric furrow ingression (Mukhina et al. 2007). Imaging of cytokinesis in intact tissues and three-dimensional cell culture models, together with experimental perturbations of specific protein function should provide insights on whether this or similar mechanisms could indeed operate. Concluding remarks Cytokinesis positioning mechanisms are very diverse in nature, even among closely related species. For example, whereas entry into and progression through S phase and mitosis are regulated by highly conserved mechanisms in all eukaryotes, the mechanisms regulating division site positioning are tailor-made to suit the morphology and function of various cell types, some of which depend on the mitotic apparatus, while others do not. Similarly, molecules with highly divergent properties regulate cytokinesis positioning even within cylindrically shaped bacteria. Furthermore, although division along the shortest

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cellular axis is typically observed in prokaryotes and many eukaryotes, cells of some unicellular organisms and cells within the confines of the tissue also divide along the long axis of cells. Although the machinery for cell division exhibits some conservation, cells use a mixand-match of stimulatory mechanisms that help position the division site and inhibitory mechanisms that help avoid incorrect locations to position the site of cytokinesis. In some instances, despite the lack of conservation of molecular components, cells appear to use similar overlapping mechanisms. For example, animal cells and fission yeast ensure positioning of the division site by stimulating equatorial actomyosin assembly as well as preventing division at incorrect locations. Thus, while some aspects of the regulation of positioning cytokinesis have emerged from studies in model organisms and systems, understanding the mechanisms operating in a variety of intact tissues represents a major challenge. Acknowledgments
We thank all members of the Balasubramanian and Oliferenko laboratories for discussion, and Wanzhong Ge, Ramanujam Srinivasan, Meredith Calvert, and Mithilesh Mishra for critical reading of the manuscript. Work in the laboratories of M.K.B. and S.O. is supported by research funds from Singapore Millennium Foundation and the Temasek Life Sciences Laboratory.

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