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    10.1101/gad.1772009Access the most recent version at doi :2009 23: 660-674Genes Dev.

    Snezhana Oliferenko, Ting Gang Chew and Mohan K. Balasubramanian

    Positioning cytokinesis


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    Positioning cytokinesisSnezhana Oliferenko, 2 Ting Gang Chew, and Mohan K. Balasubramanian 1

    Temasek Life Sciences Laboratory and the Department of Biological Sciences, National University of Singapore, Singapore117604, Singapore

    Cytokinesis is the terminal step of the cell cycle duringwhich a mother cell divides into daughter cells. Often,the machinery of cytokinesis is positioned in such a waythat daughter cells are born roughly equal in size.However, in many specialized cell types or under certainenvironmental conditions, the cell division machinery isplaced at nonmedial positions to produce daughter cells

    of different sizes and in many cases of different fates.Here we review the different mechanisms that positionthe division machinery in prokaryotic and eukaryoticcell types. We also describe cytokinesis-positioning mech-anisms that are not adequately explained by studies inmodel organisms and model cell types.

    Cytokinesis is the terminal step in the cell cycle whenbarriers in the form of new membranes (and cell walls insome cases) are generated, so as to divide a mother cellinto two daughter cells. Studies of cytokinesis havelargely focused on three major questions: (1) What is themachinery that physically divides a cell? (2) How andwhere in the cell is this machinery positioned? and (3)What regulates the timing of assembly of new mem-branes (and cell wall) such that the process of cytokinesisdoes not cause inadvertent damage to the genetic mate-rial? Several excellent recent reviews focus on the de-scription of the machinery that various cell types use forcytokinesis as well as the cell cycle regulation of cytoki-nesis (McCollum and Gould 2001; Guertin et al. 2002;Wang 2005). In this article, we will briefly introduce thecell division machinery but will largely focus on themechanisms of its positioning.

    The cytokinetic machinery

    In all cell types, elements of the cytoskeleton assembleinto distinct supramolecular assemblies to facilitate celldivision (Fig. 1). A summary of molecules participating incytokinesis in various organisms is provided in Table 1. Inanimal, 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 planeperpendicular to the axis along which the chromosomesare segregated (Schroeder 1968, 1973; Fujiwara andPollard 1976; Mabuchi and Okuno 1977; Marks et al.1986; Balasubramanian et al. 1992; Bi et al. 1998).Constriction of this so-called actomyosin or contractilering generates the forces necessary for the cleavage of

    a mother cell into two daughters. Constriction of the ringis precisely coordinated with membrane traffickingevents such that the new membranes and cell walls (infungi) are added in concert with ring constriction. Innearly all bacteria, the tubulin-like protein FtsZ assem-bles into a ring structure that is perpendicular to the axisof chromosome segregation (Bi and Lutkenhaus 1991).This so-called Z-ring is attached to the overlying plasmamembrane via integral membrane proteins (Hale andde Boer 1997; Pichoff and Lutkenhaus 2005). Althoughmolecular motors resembling the canonical eukaryoticmicrotubule-based motors, such as kinesins and dyneins,have not been discovered in bacteria, the Z-ring serves torecruit proteins important for division septum assembly.

    Septum assembly then ensues in coordination withconstriction of the bacterial Z-ring. Although a contrac-tile actomyosin-based apparatus has not been discoveredin plants, microtubules organize into two mirrored bun-dles that serve to recruit machinery important for assem-bly of new membranes and cell wall. These dynamicmicrotubules interact with F-actin filaments to assemblethe so-called phragmoplast, a structure essential forcytokinesis in plant cells (Gunning and Wick 1985). Incontrast to cytokinesis events in bacteria, yeast, fungi,and animal cells, where membranes and cell wall mate-rial are added centripetally, new membrane assembly inplant cells occurs by a process of centrifugal expansionwherein 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 formationof equally sized daugh-ter cells. However, in many instances during development(both in single and multicellular organisms), cell divisionproduces daughters of unequal sizes and differing fates. Forexample, under poor nutritional conditions, the soil bacte-rium Bacillus subtilis divides asymmetrically to producea small spore, which is capable of withstanding harsher

    [Keywords : Animal; bacteria; cleavage furrow; cytokinesis; plant; yeast;fungi]Corresponding authors.1 E-MAIL [email protected]; FAX 65-6-872-7012.2 E-MAIL [email protected]; FAX 65-6872-7007.Article is online at

    660 GENES & DEVELOPMENT 23:660674 2009 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/09;

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    environmental conditions. During such a sporulationprocess, B. subtilis cells ignore the medial division sitetypically chosen during vegetative growth, and insteadassemble a Z-ring at nonmedial locations in the cell. Inthe budding yeast Saccharomyces cerevisiae , every celldivision event results in the formation of a smaller anda larger cell, each of which inherits a different fate, withthe larger cell (mother cell) capable of switching itsmating type, while the smaller cell (daughter cell) isincapable of doing so. Asymmetric cell divisions are alsofrequently observed in metazoan cells, in which thelarger and smaller daughter cells inherit different fates.Since asymmetric cell division events (at nonmedialcellular locations) increase the chances of the geneticmaterial being damaged by the constricting cell divisionapparatus, such divisions are largely accompanied bymechanisms that help capture the DNA-segregatingapparatuses in both prokaryotic and eukaryotic cells.

    Despite the diversity of division site-positioning mecha-nisms, it appears that in most organisms, more than onemechanism functions to ensure fidelity of division siteplacement. In many instances in eukaryotic cells, suchfidelity is established by overlapping activatory andinhibitory mechanisms. In contrast, in prokaryotes, over-lapping negative regulatory mechanisms solely participatein division site selection, and stimulatory mechanismshave not been described. We will now describe in somedetail division site placement mechanisms in variousorganisms.


    Bacteria exhibit a bewildering biodiversity; as a result, nobacterium in particular serves as a model to understandbacterial cell division in general. However, given the vastnumber of studies in the Gram-negative bacterium Escher- ichia coli and the Gram-positive bacterium B. subtilis , wefocus on the mechanism of division site selection in these

    species. In E. coli and B. subtilis , which are cylindrical inshape, division site selection depends on two overlappinginhibitory mechanisms (Fig. 2). The Mini-cell (Min) sys-tem (de Boer et al. 1989) prevents assembly of the Z-ring atthe cell ends, while the process of nucleoid occlusionprevents Z-ring assembly in the vicinity of the nucleoids(chromosomal DNA) (Goehring and Beckwith 2005). Cy-tokinesis has also been studied extensively in Caulobacter crescentus , where a novel protein MipZ, unrelated to theMin 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 Minsystem include two components, MinC and MinD, whichlocalize 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; Dajkovicet al. 2008). The spatial restriction of MinC and MinDgene products to the cell poles is achieved by two un-related proteins, MinE in E. coli (Raskin and de Boer 1997,1999; Fu et al. 2001; Hale et al. 2001; Shih et al. 2003) andDivIVA in B. subtilis (Edwards and Errington 1997;Edwards et al. 2000). In addition, in B. subtilis , the novelprotein MinJ appears to participate in linking MinCD toDivIVA (Bramkamp et al. 2008; Patrick and Kearns 2008).MinD is an ATPase, which in its ATP-bound form bindscell membranes at the cell poles. MinD-ATP at the cell

    Table 1. Protein families participating in cytokinesis

    Actin Myosin Tubulin Kinesin Dynein

    Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis Homologs Cytokinesis

    Animal Yes Yes Yes Yes Yes Yes Yes Yes Yes YesPlant Yes Yes Yes No Yes Yes Yes Yes No NoYeast Yes Yes Yes Yes Yes Yes a Yes Yes b Yes Yes b

    Bacteria Yes (MreB) No No No Yes (FtsZ) Yes No No No NoProtozoa Yes No Yes No Yes Yes Yes Yes Yes Yesa Functions in nuclear positioning in fission yeast.b Functions in mitotic spindle positioning and cytokinetic fidelity in budding yeast.

    Figure 1. Assembly of cytoskeletal proteins into cytokineticmachineries in different cell types. A contractile ring composedmainly of F-actin and myosin is used for cytokinesis in animalcells and fungi. In bacteria, a tubulin-like protein FtsZ assemblesinto a ring-structure at the division site. Plant cells use a micro-tubule-based machinery known as the phragmoplast for celldivision.

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    ends recruits MinC, which prevents Z-ring assembly byits ability to bind and prevent polymerization of FtsZ (Huet al. 1999; Pichoff and Lutkenhaus 2001; Shiomi andMargolin 2007; Dajkovic et al. 2008). The boundary of theMinCD-containing zone at the cell poles is established byMinE, a protein that has the potential to displace MinCfrom MinD and stimulate its ATPase activity, therebycausing the release of MinD-ADP from membranes at thecell 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 giventime in E. coli . However, the E. coli Min system exhibitsa 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 leadsto its association with each of the cell ends for shortperiods of time, which in turn prevents Z-ring assemblyat both ends of the cell (Raskin and de Boer 1999; Fu et al.2001; Shih et al. 2003). In contrast, the Min system doesnot display an oscillatory behavior in B. subtilis and ispermanently associated with both cell poles by interac-tion 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, theB. subtilis proteins appear to prevent FtsZ-ring assemblyonly in the vicinity of the new cell poles created asa result of cell division (Gregory et al. 2008). Theevolutionary benefits of an oscillatory Min system overa Min system anchored to both cell poles are not un-derstood.

    Studies in B. subtilis have shown that the establish-ment and maintenance of the position of the division siteis a continuous process. Upon transfer to poorer nutri-tional conditions, B. subtilis cells undergoa developmentalprogram in which a mother cell divides asymmetricallyto produce a smaller spore. Time-lapse studies of sporu-lating cells have shown that medially organized Z-rings,assembled during vegetative growth, unravel into spiralsthat eventually accumulate and organize Z-rings at bothends of the cell, although only one of these matures, andonly one spore is generated (Ben-Yehuda and Losick2002). Under conditions of sporulation, levels of MinCD

    are significantly reduced (Perry and Edwards 2004), whichin turn permits Z-ring assembly in the vicinity of the cellends. Interestingly, DivIVA, which normally functions toretain MinCD at cell ends, is retained at cell ends in theabsence of MinCD. In the absence of MinCD, cell pole-localized DivIVA performs a novel second function andcaptures the origin of chromosome replication (OriC)by localizing a novel protein RacA to the cell poles(Thomaides et al. 2001; Wu and Errington 2003; Perryand Edwards 2004), so as to allow efficient segregation of a copy of the replicated chromosome into the smallerdaughter (spore) cell. Curiously, sporulating wild-typeBacillus cells, but not E. coli min-mutants, accumulatea full component of the genome into the smaller daughtercells. These observations might underscore the impor-tance of a mechanism that captures the DNA segregationmachinery in organisms that have evolved to undergoasymmetric cell divisions, even in prokaryotes (Ben-Yehuda et al. 2003, 2005). Interestingly, C. crescentus ,which divides asymmetrically, uses a DNA-binding pro-tein, ParB, to efficiently capture origins of DNA replica-tion to achieve proper spatial coordination of DNAsegregationand cytokinesis (Bowmanet al.2008;Ebersbachet al. 2008).

    Although the Min system represents the primarymechanism of division site placement in many cylindri-cal bacteria, several studies have shown that the presenceof nearby nucleoids also prevents assembly of Z-rings(Woldringh et al. 1991; Yu and Margolin 1999; Sun andMargolin 2004). Two unrelated DNA-binding proteins,SlmA (E. coli ) (Bernhardt and de Boer 2005) and Noc(B. subtilis ) (Wu and Errington 2004), have been shownto represent key effectors of nucleoid occlusion. Al-though the biochemical basis of Noc function remainsunknown, SlmA appears to affect Z-ring assembly bydirectly interacting with FtsZ (Bernhardt and de Boer2005). It is possible that such interactions between effec-tors of nucleoid occlusion and FtsZ might prevent asso-ciation of FtsZ-polymers with the cell membranes overnucleoids.

    While current studies have provided a fairly good viewof mechanisms of division site placement in cylindricalbacteria, FtsZ- and Z-rings are also used for cell divisionin spherical bacteria. Although fewer studies have fo-cused on spherical bacteria, it appears that Min or Min-like systems might participate to detect slight alterationsin spherical morphology (Huang and Wingreen 2004),thereby determining a long DNA segregation axis, per-pendicular to which the Z-ring could be assembled. Acanonical Min system has been described in Neisseriaand Deinococcus (White et al. 1999; Ramirez-Arcos et al.2001). Furthermore, Min-proteins have been shown toundergo oscillations in random orientations in sphericalmutant cells of E. coli (Corbin et al. 2002). AlthoughMinC- and MinD-like proteins have not been identifiedin Staphylococcus and Streptococcus , as-yet-unidentifiedfunctional homologs of the Min system might exist inthese bacteria. It is therefore likely that Z-ring positioningin spherical bacteria might also be under negative regu-lation by Min and Min-like proteins. Although relatively

    Figure 2. Selection of the division site by two overlappinginhibitory mechanisms in cylindrical bacteria. The Min systemprevents FtsZ ring assembly at the cell ends, and the nucleoidocclusion machinery prevents FtsZring assembly in the vicinityof the nucleoids.

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    unexplored, nucleoid occlusion might also participate inZ-ring positioning in spherical bacteria.

    Eukaryotic cells

    Division site positioning in eukaryotes utilizes diverse

    machinery and is established at different points in the cellcycle in different organisms. For example, the site of celldivision is selected in interphase in the yeasts S. cerevisiae(in G1) and Schizosaccharomyces pombe (in G2). Incontrast, 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 (inprometaphase) in plant cells. Furthermore, cell divisiongenerates daughters of equal size in some organisms andcell types, whereas in other organisms and cell types, thisprocess generates daughters of differing sizes and fates.This diversity of cell cycle and spatial regulation has led tothe evolution of several mechanisms that participate in theestablishment of the site of cell division in eukaryotic cells.

    Mitotic apparatus-independent positioningof cytokinesis

    Budding yeast S. cerevisiae

    S. cerevisiae cells grow and divide using a process of budding. At G1/S, cells assemble cortical landmarkproteins, which recruit the growth machinery composedof, among others, the Cdc42 GTPase, proteins requiredfor the assembly of F-actin patches, and the machinerytargeting secretion to this incipient site from whichgrowth via a bud wouldoccur. The position of the corticallandmark assembly depends on the mating type of the

    cells. Cells of the mating types a or a , which are typicallyhaploid, grow by the assembly of buds at axial locationsthat are positioned adjacent to the site of the previousdivision 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 celldivision (Fig. 3; Chant and Herskowitz 1991; Chant1999; Casamayor and Snyder 2002). Cytokinesis and celldivision 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 cellcycle, dictates the site of cytokinesis, the mitotic appa-ratus does not play any appreciable role in the positioningof the division site in this organism, but instead functionslater to ensure correct positioning of daughter genomeswith respect to the division site.

    The site of bud assembly is marked by landmarkproteins such as Bud3p, Bud4p, Bud10p, and Axl1p inthe case of axial budding (Chant 1999; Casamayor andSnyder 2002), and Bud8p and Bud9p in the case of bipolarbudding (Fig. 4; Harkins et al. 2001). These landmarkproteins 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 theCRIB domain-containing proteins Gic1p and Gic2p, ulti-mately leading to the assembly of septins at the futurecell division site (Iwase et al. 2006). Septins, in turn, serveto recruit the bud-site marker proteins to the regionadjacent to the division site. Rga1p, a GTPase-activatingprotein for Cdc42p, localizes to the division site so as toensure that a previously used division site is not reusedfor polarized growth and cell division (Tong et al. 2007).

    Since the cell division site is chosen early in the cellcycle, and since cells do not have a default axis to allowmaximal elongation of the mitotic spindle, budding yeastcells possess a robust mechanism that captures themitotic spindle, thereby allowing migration of one of the daughter nuclei into the bud. This spindle capture isachieved by the localization of Kar9p and a dynein,Dyn1p, to one of thespindle pole bodies andasters, causinga type V myosin-dependent movement of the SPB/astercontaining 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 alongthe motherbud axis delays activation of the Mitotic ExitNetwork (MEN), which is essential for cytokinesis, untilproper 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 byplacement of an actomyosin ring and a division septumthat divides a mother cell into two roughly equally sizedcells. The division site placement principally depends onthe position of the premitotic nucleus (Paoletti and Chang2000). The division site in fission yeast is chosen in late G2phase and is dynamic, in that alterations in the position of the nucleus until early mitosis cause repositioning of thecell division site as well (Daga and Chang 2005; Tolic-Nrrelykke et al. 2005).

    Division site selection in fission yeast involves interplaybetween 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 asthe landmarks to position the bud site at axial locations.Diploid cells select the bud site using Bud8p and Bud9p aslandmarks and undergo bipolar budding either at proximal ordistal locations.

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    morphology and the medially positioned nucleus (Sipiczkiet al. 2000; Daga and Chang 2005; Ge et al. 2005). Theanillin-related protein, Mid1p, stimulates actomyosin ringassembly at the cortex overlying the nucleus (Motegi et al.2004), while a host of so-called tip factors simultaneouslyinhibit cytokinesisat cell ends (Celton-Morizuret al. 2006;Padte et al. 2006; Huang et al. 2007). The cylindrical shapeof fission yeast cells is established by F-actin-dependentassembly of cell wall components. Elements of the F-actincytoskeleton, Cdc42-GTPase, and the machinery involvedin a -glucan and b -glucan synthesis, are all important forthe establishment and maintenance of cylindrical cellularshape (Diaz et al. 1993; Miller and Johnson 1994; Verdeet al. 1998). The cylindrical shape of the cell allowsspontaneous organization of anti-parallel bundles of microtubules, with a region of overlap of minus ends inthe medial region of the cell (Carazo-Salas and Nurse 2006;Daga et al. 2006; Terenna et al. 2008). Since these regionsof overlap aremostly associated with the nuclear envelope,spontaneous organization of microtubules within theconfines of a cylindrical shape ensures medial positioningof the nucleus (Tran et al. 2001).

    The positioning of the nucleus dictates the site of celldivision via the PH domain-containing protein Mid1p

    (Fig. 6; Sohrmann et al. 1996; Paoletti and Chang 2000).Mid1p is a membrane-associated protein related to meta-zoan anillins in terms of domain organization. Mid1pshuttles between the nucleus and the cell cortex, local-izing to the nucleus during most of interphase and to theoverlying cortex in late G2 and early mitosis (Paoletti andChang 2000). Mid1p recruits several components of theactomyosin ring to the medial region of the cell so as toallow actomyosin ring assembly overlying the position of the interphase nucleus (Motegi et al. 2004). Mid1p isexported from the nucleus upon entry into mitosis byphosphorylation by the Polo-family protein kinase, Plo1p(Bahler et al. 1998). Consequently, plo1 mutants also aredefective in division site placement (Bahler et al. 1998).The polarity factors Tea1p, Pom1p, and Tea4p, whichlocalize to the cell ends, prevent accumulation of Mid1pat one of the cell ends (the new end, which is generatedfollowing cell division) (Celton-Morizur et al. 2006; Padteet al. 2006). How Mid1p is excluded from the other (older)end remains unknown. Cells lacking Mid1p, despite themispositioning of the division septum, do not assemblesepta at the ends of the cell (Huang et al. 2007). In-terestingly, thistipocclusion ofseptation isalsoachievedvia Tea1p, Tea4p, and Pom1p. It appears that Tea1p,Tea4p, and Pom1p delay septum assembly, by down-regulating function of the F-BAR protein Cdc15p, untilactomyosin rings misplaced in the absence of Mid1p exitthe cell ends (Huang et al. 2007). It is likely that sucha mechanism might contribute to the fidelity of cytoki-nesis in smaller cells, where the ends are nearer to themid-cell site. The protein kinase Kin1p has also beenshown to participate in division placement, althoughmechanistic details are presently unknown (La Carbonaand Le Goff 2006).

    Templated cytokinesis along cellular long axis in Trypanosoma brucei

    The African protozoan T. brucei has a highly organizedand polarized cellular structure. It contains a single Golgibody and a single mitochondrion, which are located atspecific intracellular positions. Correct positioning of the division machinery is thus crucial for the faithfulinheritance of a nucleus and one each of these organ-elles. Curiously, there is no evidence at present for the

    Figure 5. Coordination of spindle orientation and cytokinesisby the MEN in budding yeast. A GTPase-driven signalingpathway, MEN is kept inactive when the mitotic spindle isnot positioned at the neck region connecting the mother anddaughter cells. Once the mitotic spindle is aligned along themother and bud axis, MEN is activated to promote mitotic exitand cytokinesis.

    Figure 4. Positioning of the division site in the budding yeast.A zone of inhibition is established by the Cdc42p GTPaseactivating protein Rga1p at the previous bud site. The landmarkproteins are then recruited to the presumptive bud site. Theselandmark proteins help to recruit a Ras-related protein, Rsr1p,which leads to the recruitment of Cdc42p GEF Cdc24p, causinglocal activation of Cdc42p. The activated Cdc42p then recruitsthe CRIB domain-containing proteins, Gic1p and Gic2p, andleads to the assembly of septins at the division site. Septins, inturn, promote actomyosin ring assembly at the division site.Rga1p then localizes to the division site to ensure that a pre-viously used division site is not reused for polarized growth andcell division.

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    existence of an actomyosin-based cytokinetic apparatusin T. brucei .

    In T. brucei , a single flagellum is attached to the cellbody via the flagellum attachment zone (FAZ) (Kohl et al.1999). During cell cycle progression, the old flagellumguides 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, andthe 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 (andits associated FAZ) promotes cytokinesis from the ante-rior end of the cell (Fig. 7; Vaughan and Gull 2003). T.brucei mutants that are defective in intraflagellum trans-port (IFT) have a shorter new flagellum and, interestingly,undergo unequal cell division (Kohl et al. 2003). Thus, thelength of the flagellum of T. brucei increases by IFT andthe flagellar length affect the position of cleavage furrow.

    Procyclic cells of T. brucei in the tsetse fly midgutundergo a few rounds of symmetrical cell division andthen differentiate into an epimastigote form while mi-grating toward the salivary glands (Sharma et al. 2008).This differentiation process also involves an asymmetriccell division in which a long cell and a short epimastigotecell are produced. The procyclic T. brucei increases itscell body length to almost double its original length priorto the asymmetric cell division, and a short new flagel-lum is grown from the posterior end (Sharma et al. 2008).Ingression of the cleavage furrow from the distal tip of theshort new flagellum leads to the production of twodaughter cells with different cell sizes (Sharma et al.2008). Division along the long axis is also observed in

    other Trypanosomal species as well as in other organismssuch as Leishmania major , although mechanisms un-derlying division site placement in these organisms arenot well understood.

    Establishment of the division plane in plant cells

    Plant cells are encased by cell wall material and, unlikeanimal cells, are unable to migrate. Thus, proper organi-zation of pattern and morphology of plant tissues dependslargely on the precise positioning of the division plane.Improper specification of the division plane in plant cellsresults in missegregation of cell fate determinants anddefective tissue morphology and patterning.

    In contrast to animal cells that use an actomyosin-based contractile ring for cytokinesis, plant cells mainlyuse microtubule-based structures for cell division. Inaddition to the mitotic spindle, two additional microtu-bule-based cellular structures known as the preprophaseband (PPB) and phragmoplast play crucial roles in plant

    cytokinesis (Gunning and Wick 1985). PPB is a ring-likestructure composed of microtubules and F-actin that ispositioned underneath plasma membrane and circum-scribes the premitotic nucleus. In contrast, the phragmo-plast is a structure assembled during cytokinesis thatconsists of two parallel microtubule bundles separated bythe expanding cell plate in the middle.

    In most plant cell types, an array of parallel microtu-bule bundles oriented perpendicular to the cells long axisis organized underlying the cell cortex during interphase(Fig. 8). This cortical microtubular array contributes ininterphase to the formation of PPB, whose positioncorresponds to that of the future division site (Hardhamand Gunning 1978; Mineyuki et al. 1999). Thus, similar

    to yeast cells, plant cells specify their division planebefore entering mitosis. As the cell cycle proceeds, the

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

    Figure 6. Division site selection in the fission yeast S. pombe .The division site is determined by the position of the premitoticnucleus in fission yeast through Mid1p, an anillin-related pro-

    tein. Mid1p shuttles between nucleus and cell cortex duringinterphase. Upon entry into mitosis, Polo-related kinase Plo1ppromotes the exit of Mid1p from the nucleus to specify thedivision zone. The cortically localized Mid1p then promotesassembly of the actomyosin ring at the division site. Duringcytokinesis, a tip complex prevents septum assembly at the cellends.

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    parallel cortical microtubular array condenses at the cellcortex overlying the premitotic nucleus. Several studieshave suggested that the nuclear position determines theposition of PPB and the future division site (Murata andWada 1991; Gimenez-Abian et al. 2004). Displacementof the interphase nucleus triggers the establishment of the PPB and the division site close to the new nuclearposition (Murata and Wada 1991). Upon entry intomitosis, the PPB disassembles, and F-actin is depletedfrom the cortical region occupied by the PPB (Cleary1992, 1995; Liu and Palevitz 1992). It has been proposedthat the loss of microtubules and F-actin from the PPBleads to the accumulation of a landmark protein to markthe future division site. After chromosome segregation,the remnants of the anaphase spindle form the phragmo-plast, which then expands laterally toward the corticalarea occupied by the PPB. Vesicular trafficking andfusion, targeted by microtubule bundles at the edge of phragmoplast, lead to the formation of cell plate. Aftercompletion of cytokinesis, the microtubule bundles reor-ient their position to reform the parallel cortical micro-tubular array in the two newly separated daughter cells.

    The question of how the PPB defines the future divisionplane 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 proteinmight function as the long-sought landmark protein thatmarks the division plane after PPB disassembly (Smithet al. 1996; Walker et al. 2007). Maize mutants defectivein TANGLED function have a misoriented division plane,as the phragmoplast is not guided toward the cortexdefined by PPB (Cleary and Smith 1998). A similar butweaker phenotype has been observed in the Arabidopsistan mutant, in which a population of root-tip cells displaytilted division planes that are unable to form a cell plateperpendicular to cells long axis. Arabidopsis TANGLEDis recruited by microtubules and kinesins to the corticalregion occupied by the PPB during interphase (Walker

    et al. 2007). Once localized to the cortex, TANGLEDpersists after the PPB is disassembled and remains at thefuture division site in a microtubule-independent manner(Walker et al. 2007). It then guides the expanding phrag-moplast to the cortical area previously occupied by PPBduring cytokinesis. How TANGLED guides the phragmo-plast expansion toward the PPB-marked cortex remainsunclear. It has been hypothesized that TANGLED resem-bles vertebrate adenomatous polyposis coli (APC) pro-teins and might potentially interact with EB1 at the plusends of microtubules radiating from the phragmoplast.Future studies should identify the precise mechanisms bywhich TANGLED and related proteins function. Never-theless, the presence of TANGLED protein in bothmonocots and dicots suggests that a conserved mecha-nism might specify the division zone in plants.

    Mitotic apparatus-dependent division site positioningin animal cells

    Cytokinesis in animal cells is achieved by constriction of the cortex between the two sets of segregated chromo-somes. Many models have been suggested over the yearsto explain how cortical activity could be regulated: Anexcellent historical overview of cytokinesis studies in19th and 20th centuries can be found in Rappaport (1986).It was eventually established that cytokinesis is initiatedby signal(s) emitted from the mitotic apparatus. When themitotic spindle in starfish eggs was pushed or rotated, thecortical contractile ring was assembled at a new position,corresponding to that of the spindle (Rappaport andEbstein 1965; Rappaport and Rappaport 1993). Theseexperiments demonstrated that the cortex of the echino-derm eggs is initially capable of furrowing at any location,

    but the orientation and position of the spindle determinethe actual division plane. Therefore, the current view isthat microtubules associated with the spindle apparatusplay a crucial role in controlling furrow positioning andingression. During anaphase, the mitotic spindle in mostanimal cells contains a set of bundled microtubules(central spindle) and two radial arrays of astral micro-tubules. Each of these arrays differentially controls acto-myosin cortical activity and can induce furrow formation(Fig. 9). However, they often cooperate to induce furrow-ing specifically between separated chromosomes. Theexact contributions of these various microtubular arraysdiffer among cell types.

    Regulation by astral microtubulesIt appears that in cells that have large asters, the astralmicrotubules play an important role in the determinationof the cleavage plane. It has been proposed that astralmicrotubules may provide inhibitory signals to the polarcortical regions, resulting in local inhibition of contrac-tility and establishment of the gradient of cortical ten-sion. In such a manner, the highest tension and corticalfurrowing would be thenrestricted to cell equator(Wolpert1960; White and Borisy 1983). These models are cumula-tively known as polar relaxation models. Consistently,a complete lack of microtubules leads to the enhanced,

    Figure 8. Establishment of the division plane in plant cells.Microtubule bundles underlying cell cortex are oriented perpen-dicular to the cells long axis during interphase. The microtu-bule array condenses, and a PPB is formed underneath plasmamembrane, whose position predicts the future division site.Upon entry into mitosis, the PPB is disassembled, and F-actin isdepleted from the cortical region occupied by the PPB. Land-mark proteins such as TANGLED remain at the PPB to mark thedivision site. After mitosis, a microtubule-based structure,termed the phragmoplast, is formed and expands laterally to-ward the cell cortex region occupied by the PPB. Targetedvesicular trafficking and fusion at the phragmoplast lead to the

    assembly of cell wall at the division site.

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    although disorganized, cortical contractility (Canmanet al. 2000; Paluch et al. 2005).

    On the other hand, classic experiments of Rappaport onshaping the sand dollar eggs into toruses suggested that itis the equatorial zone where microtubule asters convergeat the cortex that determines position of the cleavagefurrow (Rappaport 1961). Theories that propose thata subpopulation of mitotic asters stimulate the futurefurrow region, possibly through delivery of a factor that

    could be transported along microtubules, are known asastral stimulation models. In such models, activity of theproposed furrowing activator would be highest at theequatorial cortex, where asters from two spindle polesmeet. Astral stimulation has been proposed for position-ing of furrows in large cells (fertilized eggs of amphibians,birds, and fish) and in cells with several mitotic appara-tuses (insects). Mathematical modeling of astral stimula-tion correctly predicts the positioning and occurrence of furrowing when cell shape is significantly altered beforedivision (Devore et al. 1989).

    Regulation by the spindle midzone

    Cytokinetic positioning and furrowing also appear to beinfluenced by proteins residing at the spindle midzone insome cell types. The role of the spindle midzone indetermining the cleavage position was first determinedin the studies of unequal cell division in grasshopperneuroblasts. Unequally sized asters determined the asym-metric positioning of the spindle, but it was the cellcortex nearest the spindle midzone that received cleavagestimulus. Furthermore, furrowing required the continu-ous stimulation from the spindle midzone (Kawamura1977). Many studies have shown that the central spindletogether with asters are involved in the positioning of thecleavage furrow (Rappaport 1985; Cao and Wang 1996;

    Bonaccorsi et al. 1998; Mishima et al. 2002, 2004). Thus,if the spindle is off-center, the division is asymmetricwith the mother cell giving rise to two daughters of different sizes. However, in situations in which spindlesdo not have asters, like in oocytes during female meiosisin the mouse (Szollosi et al. 1972), the cleavage furrowposition is controlled solely by the central spindle.

    Transmission of the furrow positioning signals frommicrotubule arrays to cell cortex

    It appears that microtubules of the spindle apparatuscontrol cortical contractility largely by maintaining ac-tive gradients of the small GTPase Rho through thepositioning of Rho regulators on microtubules. Rho isa critical regulator of cleavage furrow induction, and itsactivity is required for cortex furrowing, as first shown byMabuchi et al. (1993), Kishi et al. (1993), and Drechselet al. (1997). Similar to its function in other actomyosin-dependent processes, active GTP-bound Rho inducesF-actin assembly (Watanabe et al. 1997) and causesactivation of myosin II function (Kimura et al. 1996) atthe cell equator, thereby promoting cortical constriction.

    Active Rho accumulates in a narrow cortical bandoverlying the mitotic spindle, and spindle displacementleads to repositioning of this cortical band of active Rho(Bement et al. 2005). Activities of Rho guanine nucleotideexchange factor (GEF), ECT2, and a proposed Rho GAP(GTPase-activating protein), Cyk4, are needed to sustainRho function in cytokinesis (for review, see Piekny et al.2005). A traditional view is that ECT2 function is initiallyrequired for the accumulation of GTP-bound Rho at thecell equator, in order to promote furrowing while down-regulation of Rho through the GAP activity inducesdisassembly of the cytokinetic machinery and promotescompletion of cytokinesis (Minoshima et al. 2003). In thismanner, it is assumed that activation of Rho and its down-regulation 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 narrowRho activity zone at the cell equator. When the GAP wasinactivated, Rho activity zones were poorly focused andexhibited unstable and often oscillatory behavior earlyduring cytokinesis, presumably triggering cytokinesis fail-ures (Miller and Bement 2009). Thus it appears that Rhoactivity zones represent not simply the zones of localactivation but zones where Rho undergoes fast GTPaseflux. Consistent with this notion, Aurora kinase thatphosphorylates Cyk4 (which otherwise exhibits a RacGAP activity) and triggers its conversion into a Rho GAP(Minoshima et al. 2003) produces a phosphorylation gra-dient that extends from the spindle midzone to the corteximmediately after anaphase onset (Fuller et al. 2008). Thusit appears that the machinery is in place to enable rapidGTPase cycles of Rho precisely at the cell equator. Thismight provide a part of the answer to an interestingquestion as to how exactly the furrowing signals are trans-mitted from the spindle midzone to the equatorial cortex,frequently on micrometer scale distances. Cytokinetic

    Figure 9. Three models for cleavage plane positioning inanimal cells. Three modes of division site positioning have beendemonstrated in animal cells. After chromosome segregation,the overlapping microtubule bundles at the cell midzone knownas the central spindle specify the cleavage plane. In certain celltypes, astral microtubules stimulate cleavage furrow formation

    at the division site, whereas in some cases, astral microtubulesinhibit cortical contractility at the cell ends to promote cleavagefurrow formation at the division site.

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    regulators, such as the Aurora BIncenpSurvivin com-plex and the central spindlin complex consisting of thekinesin-like protein MKLP1 and Cyk4, all localize to thespindle midzone during anaphase. The Aurora kinasecomplex is required for central spindlin localization andfunction (Severson et al. 2000), but it is also possible thatit may have other targets. Furthermore, control of Rhoactivity at the cleavage furrow is not limited to regula-tion by Aurora kinase. The polo-like kinase 1, Plk1,promotes recruitment of the Rho GEF, ECT2, to thecentral spindle, independently of Aurora B (Petronczkiet al. 2007). Plk1 in mammalian cells localizes to thecentral spindle through its interaction with the micro-tubule bundler PRC1 (Neef et al. 2007), which in turninteracts with several mitotic kinesins, includingMKLP1-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 beenshown to directly phosphorylate the MKLP1 (Lee et al.1995; Liu et al. 2004). Thus it appears that an interwovennetwork of proteins at the spindle midzone contributesto regulating Rho activity at the future division site.

    It is obvious from the experiments discussed above thatmicrotubules have been proposed to provide both stimu-latory and inhibitory effects on cortical stiffness andcontraction. Indeed, it appears that the mitotic apparatusis indeed capable of providing two furrow-specifyingsignals (Dechant and Glotzer2003; Bringmann and Hyman2005). How could this be achieved? An interesting view isthat the key parameters positively or negatively influenc-ing the cortical contractility are stability and possibly theconfiguration of microtubule arrays. While a subpopula-tion of dynamic astral microtubules seems to cause polarrelaxation, other, more stable microtubules (which couldbe stable astral or central spindle microtubules) stimulatecontractility at the sites where they contact the cortex(Canman et al. 2003; Chen et al. 2008; Foe and von Dassow2008; Murthy and Wadsworth 2008). Odell and Foe re-cently proposed a model wherein the dynamics of thecentral spindlin component kinesin MKLP1 are used toprovide an explanation of how the differential microtubulestability could modulate cortical contractility. In theirmodel, most MKLP1 is sequestered by a multitude of dynamic astral microtubules and does not reach the cellcortex. Therefore, Rho activation is suppressed wheredensity 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 specificallyat the cell equator (Odell and Foe 2008). This interestingmodel can indeed explain how microtubules of the spindleapparatus are capable of delivering both stimulatory andinhibitory signals to the cortex, depending on their stabil-ity and configuration.

    Setting up the division site in animal cells growing in thecontext of a tissue and the role of mitotic spindleorientation

    The purpose of cytokinesis is not limited to an increase incell number. It also shapes tissues and organisms and

    allows daughter cells to adopt distinct fates. In multicel-lular organisms, a rather simple, symmetric cell di-vision (when a mother cell divides into approximatelyequally sized daughters bearing same cellular fates) isoften oriented, and such orientation is essential to sustaina specific tissue shape and function. For instance, inanimal epithelium, the dividing cells remain in contactwith extracellular matrix and with each other, andthereby 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 torestrict damaged and oxidized proteins to the agingmother cell (Aguilaniu et al. 2003), while in complexmulticellular organisms, asymmetric division site place-ment sets specific cellular patterns that contribute toorganism development and tissue homeostasis.

    As spindle orientation in animal cells sets the plane of future cell division, much work in recent years has alsobeen dedicated to elucidating mechanisms underlyingspindle orientation both in two- and three-dimensionalcell cultures and in the context of a tissue (for reviews, seeAhringer 2003; Gonzalez 2007). We will discuss themonly briefly. When mammalian epithelial NRK cells aregrown as two-dimensional cultures, they remain non-polarized. During division their spindles appear to beoriented along the long axis of the cell (OConnell andWang 2000). A simple and appealing explanation is thatthe mitotic spindle naturally aligns with the cells longaxis due to geometric constraints and that this position-ing ensures that the cell divides along the short axis.However, it appears that when cells are grown on themicro-patterned substrates that provide defined contactsbetween cell and extracellular matrix (ECM), spindleorientation is driven not simply by cell geometry butrather by cortical marks associated with so-called re-traction fibers that are left during mitotic cell rounding.Such cortical marks are rich in various cytoskeletalproteins and reflect the status of cell/ECM contacts priorto division (Thery et al. 2005, 2007). Therefore, themitotic spindle is actively oriented with respect to cell/ECM adhesion plane or cell shape even in cells that growout of the tissue context and are considered nonpolar-ized. Contributions of cell shape and cell/ECM contactsin spindle orientation in vivo are probably not mutuallyexclusive (and these factors might be very well be in-terdependent), and both mechanisms could functiondepending on a physiological context.

    When epithelial cells are grown on permeable matrixsupport, they form a sheet-like cellular monolayer thatexhibits many properties of true epithelium. To sustainthis organization through cellular expansion, a dividingcell has to ensure that it remains in contact withsurrounding cells and with the matrix throughout furrowingression. It is therefore not surprising that most spin-dles in polarized MDCK cells are oriented perpendicularto the long, apicalbasal, axis of the cell, allowing cellcleavage to occur in the plane of the epithelium (Reinschand Karsenti 1994). Similarly, in the dorsal epiblast of the

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    zebrafish embryo, most spindles are oriented perpendic-ular to the long axis of the cell, resulting in cellulardivision along the long axis. Again, such alignmentsuggests the existence of a mechanism actively drivingspindle orientation. In epithelia, adherens junctions arelocated at lateral cell borders near the apical surface andcontain polarity determinants and microtubule-bindingproteins. Junctional complexes appear to capture astralmicrotubules, and forces generated by dynein couldrotate spindles into alignment. Therefore, adherens junc-tions could provide the link between cell polarity andspindle orientation (Lu et al. 2001). Mutations thatdisrupt spindlecortex interactions can induce abnormaldivisions and contribute to hyperproliferation of daughtercells (Yamashita et al. 2003, 2007; Yamashita and Fuller2005,2008).In thezebrafish embryo,injectionof dominant-negative Dishevelled or down-regulation of Wnt pathwaycomponents (Wnt11 and Stbm) causes randomization of division orientation, implicating noncanonical Wnt sig-naling pathway in controlling this process (Gong et al.2004). Thus, the axis of division may be defined bymitotic spindle orientation that in turn is driven bycellcell signaling and apicalbasal polarity cues (see alsoSchlesinger et al. 1999; Schober et al. 1999; Petronczkiand Knoblich 2001 and others).

    Cell division in animal tissues: further questionsand challenges

    Orientation of cell division in tissues can be specificallyregulated in space and time to achieve the right balance of cell expansion and cell differentiation. For instance, inmouse embryonic skin, some cells eventually start di-viding perpendicular to the basement membrane, yield-ing two daughters, one of which remains in the plane of the initial cell layer and the other becomes a so-calledsuprabasal cell. The number of such cells increases asskin stratification proceeds. When divisions proceedlaterally to the basement membrane, skin stratificationdoes not occur. Again, it appears that the plane of celldivision is primarily determined by spindle orientation,which requires function of the Pins homolog LGN andthe inscuteable homolog mInsc. While LGN and mInscconstitute the cell polarity cues, p150glued, a subunit of dyneindynactin complex, seems to function togetherwith the spindle pole-anchoring protein NUMA to createpulling forces that could position the spindle (Lechler andFuchs 2005). It would be of great interest to continueinvestigating the processes of spindle alignment anddivision site positioning in mouse animal models, look-ing at cell division in the tissue context. Yet, results of gene deletions and other gene manipulations could benotoriously difficult to interpret because of tight feedbackbetween planar polarity and spindle orientation.

    Curiously, it was observed that during cytokinesis inpolarized epithelial cells of mouse gastral crypts, spindlesare oriented parallel to the tissue and close to the apicalsurface, but furrow ingression starts from the basolateralsurface and, in fact, far away from either midspindle orastral microtubules (Fig. 10; Bjerknes and Cheng. 1989;

    Fleming et al. 2007). Furthermore, spindle remnants andmidbodies were always seen at the apical cell borders andnever at the basal or lateral borders in late telophase cells,suggesting that furrowingression proceeds in asymmetricfashion starting at the basal side and ending at the apicalsurface (Das et al. 2003; Royou et al. 2004; Fleming et al.2007). So how could the spindle apparatus direct furrowingression? Is furrowing initiated basolaterally by un-known mechanisms and then sustained through inter-actions with spindle and astral microtubules? In thislight, it might be useful to recall the polar relaxationmodel, wherein relaxation of part of the cortex allowsfurrow ingression to occur. It would be interesting toevaluate whether such a mechanism could function inthe confines of the epithelial cell geometry. It might alsobe possible that other factors, such as local activation of actin depolymerization or loss of actin cytoskeletoncross-linking, could result in a similar functional out-come. For instance, it has been shown that depletion of the actin cross-linking protein a -actinin leads to a highlyunstable cortex and asymmetric furrow ingression(Mukhina et al. 2007). Imaging of cytokinesis in intacttissues and three-dimensional cell culture models, to-gether with experimental perturbations of specific pro-tein function should provide insights on whether this orsimilar mechanisms could indeed operate.

    Concluding remarksCytokinesis positioning mechanisms are very diverse innature, even among closely related species. For example,whereas entry into and progression through S phase andmitosis are regulated by highly conserved mechanisms inall eukaryotes, the mechanisms regulating division sitepositioning are tailor-made to suit the morphology andfunction of various cell types, some of which depend onthe mitotic apparatus, while others do not. Similarly,molecules with highly divergent properties regulate cy-tokinesis positioning even within cylindrically shapedbacteria. Furthermore, althoughdivision along theshortest

    Figure 10. Cytokinesis along the cellular long axis in polarizedintestinal epithelial cells. In most cultured cell lines, the di-vision plane is positioned perpendicular to the cells long axis. Invivo, the polarized intestinal epithelial cells, however, dividealong the cells long axis.

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    cellular axis is typically observed in prokaryotes andmany eukaryotes, cells of some unicellular organismsand cells within the confines of the tissue also dividealong the long axis of cells. Although the machinery forcell division exhibits some conservation, cells use a mix-and-match of stimulatory mechanisms that help positionthe division site and inhibitory mechanisms that helpavoid incorrect locations to position the site of cytoki-nesis. In some instances, despite the lack of conservationof molecular components, cells appear to use similaroverlapping mechanisms. For example, animal cells andfission yeast ensure positioning of the division site bystimulating equatorial actomyosin assembly as well aspreventing division at incorrect locations. Thus, whilesome aspects of the regulation of positioning cytokinesishave emerged from studies in model organisms andsystems, understanding the mechanisms operating ina variety of intact tissues represents a major challenge.

    AcknowledgmentsWe thank all members of the Balasubramanian and Oliferenkolaboratories for discussion, and Wanzhong Ge, RamanujamSrinivasan, Meredith Calvert, and Mithilesh Mishra for criticalreadingof the manuscript. Work in the laboratories of M.K.B. andS.O. is supported by research funds from Singapore MillenniumFoundation and the Temasek Life Sciences Laboratory.


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