Cytokinesis in fission yeast: A myosinpas de deux

Cytokinesis in Fission Yeast: A Myosin pas de deux1

DANIEL P. MULVIHILL, THEIN Z. WIN, THOMAS P. PACK, AND JEREMY S. HYAMS*Department of Biology, University College London, London WC1E 6BT, United Kingdom

KEY WORDS: myosin II; Myo2; Myp2; Cdc7; Spg1

ABSTRACT Cytokinesis in the fission yeast, Schizosaccharomyces pombe consists of two dis-tinct but overlapping events: the assembly and constriction of a cytokinetic actomyosin ring (CAR)and the formation of a cross wall or septum. These two processes must be spatially and temporallycoordinated both with each other and with other cell cycle events, most notably spindle formationand anaphase chromosome segregation. In fission yeast, the CAR contains two unusual type IImyosins, Myo2, encoded by the gene myo21, and Myp2, encoded by myp21. The relationship of thesetwo proteins to each other and their relative contribution to CAR assembly and contraction islargely unknown. Here we review what is known about the role of each myosin in cytokinesis andpresent some new information concerning their regulation and possible physical interaction.Microsc. Res. Tech. 49:152–160, 2000. © 2000 Wiley-Liss, Inc.

INTRODUCTIONThe most prominent feature of the fission yeast cell

cycle, indeed the characteristic for which these organ-isms were originally named, is cell division by medialfission. Cytokinesis in fission yeasts is achieved by theformation of a cross wall or septum that bisects the cellat its volume mid-point (Miyata et al., 1986). For nor-mally growing cells that maintain a constant diameterthis is the cell equator and septation hence generatestwo identically sized daughters (Chang and Nurse,1996). This is, in fact, rather remarkable given that thegrowth of the cell leading up to cytokinesis is asymmet-ric (Mitchison and Nurse, 1985) and, moreover, thatsome of the proteins that regulate septum formationthemselves show a striking cellular asymmetry(Cerutti and Simanis, 1999). Septum formation in S.pombe is directed by a cytokinetic actomyosin ring(CAR), which is assembled coincidentally with the for-mation of the intranuclear mitotic spindle (Alfa andHyams, 1990; Kanbe et al., 1989; Marks and Hyams,1985). Equivalent structures have now been seen in awide range of fungi (Butt and Heath, 1988; Kilmartinand Adams, 1984; Momany and Hamer, 1997) and it isassumed that a CAR will be shown to be a generalfeature of fungal cytokinesis. In both S. pombe and thebudding yeast Saccharomyces cerevisiae, the CAR hasbeen shown to contain myosin II and to be contractile(Bi et al., 1998; Kitayama et al., 1997; Lippincott andLi, 1998; May et al., 1997). Thus, at least at a superfi-cial level, the underlying mechanism of cytokinesis inthese unicellular Ascomycetes is reminiscent of theequivalent process in animal cells (see elsewhere inthis volume), despite the fact that these are cells en-closed within a rigid cell wall. The demonstration thatthe fission yeast CAR contains not one but two myosinII’s, Myo2 (the product of the gene myo21; May et al.,1997; Kitayama et al., 1997) and Myp2 (the product ofthe gene myp21; Bezanilla et al., 1997; Mulvihill et al.,1999; also known as myo31, Motegi et al., 1997) was,therefore, of considerable interest. Both myosins areunusual in that their tails contain multiple prolineresidues, 9 in the case of myo21 and 27 in the case of

Contract grant sponsor: Medical Research Council; Contract grant sponsor:Wellcome Trust. Contract grant number: 046747.

*Correspondence to: Jeremy S Hyams, Department of Biology, UniversityCollege London, Gower Street, London WC1E 6BT, UK.E-mail: [email protected]

Received 24 September 1999; accepted in revised form 1 December 1999Note on terminology: In this article the wild type version of a fission yeast

gene is designated myo21, the mutant form myo2-, a strain in which a particulargene is deleted myo2D, the protein encoded by that gene Myo2. Cell division cycle(cdc) mutants are generally temperature sensitive for a particular function;these mutants grow normally at the permissive temperature (usually 25°C) butarrest at the point in the cell cycle that the gene product is used when grown atthe restrictive temperature (usually 36°C). An exception is the mutant myo2-E1,which is temperature-sensitive for septation but not for growth.

Fig. 1. Genetic evidence for the interaction of Myo2 and Myp2.Phenotype of myosin mutants in S. pombe. (a) myp2D, (b) myo2-E1,(c) the double mutant myo2-E1 myp2D. Strains were grown at thepermissive temperature (25°C) and stained with Calcofluor to revealthe structure of the septum. The myo2-E1 mutant executes cytokine-sis more or less normally when Myp2 is present but not in its absence.Bar 5 10 mm.

MICROSCOPY RESEARCH AND TECHNIQUE 49:152–160 (2000)

© 2000 WILEY-LISS, INC.

myp21 (Bezanilla et al., 1997; May et al., 1998). Thetail of the single myosin II from budding yeast, Myo1,contains 8 prolines (Watts et al., 1987). The presence ofproline residues means that the tails of these myosinsare predicted not to form the extended coiled-coil struc-ture typical of the myosin II’s. Nevertheless, they ap-pear to be able to form higher order aggregates (Beza-nilla and Pollard, 1998). Myo2 appears to be regulatedby a single light chain, the product of the gene cdc41

(McCollum et al., 1995, 1999), which is distinct fromboth the regulatory and essential light chains of themore conventional “conventional” myosins (May et al.,1998). These features lead us to suggest that the yeastmyosin II’s form a distinct subgroup within the myosinII family (May et al., 1998). However, for the presentwe assume that the analysis of CAR function in fissionyeast will generate useful insights into the mechanismof cytokinesis in more complex cells (Field et al., 1999).

Detailed genetic and molecular genetic analyses ofcytokinetic mutants in S. pombe have revealed a num-ber of other proteins that are essential for the place-ment and function of the CAR and for both the initia-tion and termination of septation (for a general account

of fission yeast cell biology see Robinow and Hyams,1989; for recent reviews of fission yeast cytokinesis seeBalasubramanian et al., 1998; Gould and Simanis,1997; Le Goff et al., 1999). In this review we pay par-ticular attention to one of these regulatory genes,cdc71, which encodes a protein kinase whose functionis essential for cytokinesis. Overproduction of the Cdc7protein induces the formation of multiple septa thatfail to complete cytokinesis (Fankhauser and Simanis,1994). Cdc7 function is under the control of a GTPase,Spg1, whose increased expression also induces septumformation (Schmidt et al., 1997). Spg1 is in turn regu-lated by a GAP (GTPase-activating protein) consistingof two proteins, Cdc16 and Byr4 (Furge et al., 1998)and loss of function of either of the latter leads tounregulated septum formation. Thus, simply put, Cdc7and Spg1 turn on cytokinesis while Cdc16 and Byr4turn it off (Cerutti and Simanis, 1999, and referencestherein). Other protein kinases that are involved in theregulation of cytokinesis include a polo-related kinaseencoded by the genes plo11 (Okhura et al., 1995) andsid21 (Sparks et al., 1999). Plo1 appears to have twodistinct cytokinetic roles: the activation of Mid1, a pro-

Fig. 2. Cytokinetic actin ring in fission yeast is contractile. Wildtype cells were transformed with a plasmid in which the N-terminusof myo21 was fused to green fluorescent protein (Myo2.NGFP). Cellswere fixed and representative images assembled to illustrate thestructural changes of the CAR through cytokinesis (top). Bottom:Same cells stained with DAPI to show the time course of mitosis. a:

Interphase cell. b,c: Early mitosis. d,e: Anaphase. f,g: Followingmitosis the daughter nuclei move back to the position that will becomethe mid-point of the daughter cells following cytokinesis. Note thatthe CAR appears sharp in e and g but diffuse in d and f, suggestingthat its orientation changes with respect to the cell axis during con-traction. Bar 5 10 mm.

153TWO TYPE II MYOSINS IN FISSION YEAST CYTOKINESIS

Figure 3

Figure 4

154 D.P. MULVIHILL ET AL.

tein that plays a major role in the placement of theCAR (B̈ahler et al., 1998) and the activation of theSpg1/Cdc7 pathway (Mulvihill et al., 1999). Sid2 on theother hand appears to function downstream of Cdc7(Sparks et al., 1999). Interestingly in this regard, wehave shown a genetic interaction between Cdc7 andboth Myo2 and Myp2 (May et al., 1997; Mulvihill et al.,1999). Here we review these and other findings relatingto the properties of the two fission yeast myosin II’s andspeculate as to their role in cytokinesis.

RESULTSCells Deleted for Myo2 Are Unable to Execute

Cytokinesis; Cells Deleted for Myp2 Show aCytokinetic Defect

The myo21 gene was independently isolated byKitayama et al. (1997) and May et al. (1997) and sub-sequently shown to correspond to rng51, a gene iden-

tified in a screen for new fission yeast mutants showinga conditional cytokinesis defect (Balasubramanian etal., 1998). Deletion of myo21 is lethal and germinatingmyo2D spores are able only to form microcolonies con-sisting of a small number of aberrantly septated cells.This lethality is partially rescued by the mutant smy2-,although the identity of the Smy2 protein is at presentunknown (May et al., 1997). The rng5- mutant (nowreferred to as myo2-E1) is viable at 36°C but is unableto complete cytokinesis and cells accumulate septa andbranch. At 25°C it divides normally (Fig. 1b). Likemyo21, myp21 was also isolated independently by anumber of groups (Bezanilla et al., 1997; Motegi et al.,1997; Mulvihill et al., 1999). Curiously, each groupreports a different phenotype for cells lacking Myp2(see Mulvihill et al., 1999). In our hands, myp2D cellsshow a mild cytokinetic defect regardless of growthconditions. About 80% of cells in a normally growingpopulation execute cell division normally but in theremainder the septum fails to bisect the two daughtercells properly (Fig. 1a; see also Fig. 4). Thus, althoughMyp2 is not essential for cytokinesis, cytokinesis pro-ceeds more efficiently in the presence of Myp2 than inits absence. This view of Myp2 function is reinforced bythe phenotype of the double mutant myo2-E1 myp2D,which shows a strong cytokinetic defect even at thepermissive temperature (Fig. 1c). This is even morepronounced, in fact, than that seen for myo2-E1 aloneat the restrictive temperature (data not shown; seeBezanilla and Pollard, 1998) and we interpret this asindicating that the function of the Myo2-E1 mutantform of Myo2 is compromised in the absence of Myp2.

Analyses of mutant phenotypes point to Myo2 play-ing an essential role in cytokinesis but the most direct

Fig. 5. CAR formation is less efficient in the absence ofMyp2. Myo2.NGFP incorporation into cytokinetic rings in awild type strain (a) and a myp2D strain (c). b and d showthe corresponding phase-DAPI images. Myo2.NGFP is re-cruited to the cell equator in myp2D but often appears as adot and not a ring. Bar 5 10 mm.

Fig. 3. Contraction of the fission yeast cytokinetic actin ring inliving cells. Cells were labelled as in Figure 2 and ring contractionfollowed in a single living cell. The time of the complete sequence was14 min. When played as a movie sequence, the ring is seen to pitchand yaw. Trails of myosin fluorescence (presumably associated withactin filaments) can be seen to extend from the CAR along the longaxis of the cell and these may be responsible for the lateral move-ments of the CAR. Bar 5 10 mm.

Fig. 4. Cytokinetic defect in myp2D cells. Time lapse sequence ofmyp2D cells growing on an agar surface and viewed by phase contrastmicroscopy. The cell in the first panel (0 min) has just undergone anabortive cytokinesis. The two daughter cells divide normally while thecell forms a branch and a second septum at the site of the originalfailed septum. The cell eventually forms a colony but this containsnumerous cells that exhibit various cytokinetic defects (final panel; 24hours). Bar 5 10 mm.


evidence has come from cells in which Myo2 or its lightchain Cdc4 were introduced into living cells as fusionproteins with green fluorescent protein (GFP). Thesechimeric proteins become incorporated into cytokineticrings whose contraction can be followed in real time(Balasubramanian et al., 1998; Kitayama et al. 1997).Figure 2 shows a sequence from a cell expressing Myo2labelled with GFP at the N-terminus (Myo2.NGFP).The CAR appears initially as a diffuse band overlyingthe nucleus before any detectable chromosome segre-gation (Fig. 2c). As anaphase proceeds, the ring sharp-ens (Fig. 2e) and then contracts (Fig. 2f,g). Living cellsfollowed in real time reveal that the ring pitches andyaws prior to contraction (Fig. 3). In the images shownin Figure 3, trails of myosin fluorescence (presumably

associated with actin) can be seen to extend from thering along the cell axis and we speculate that lateralforces may be responsible for the precise positioning ofthe ring prior to, and possibly even during, its contrac-tion.

Further evidence for the physical interaction of thetwo myosins has emerged from the analysis ofMyo2.NGFP in wild type and myp2D genetic back-grounds. In wild type cells, Myo2 rings are routinelyobserved although in some cells the protein assemblesaberrantly into an equatorial dot that appears to be anartefact of Myo2 overexpression. Myo2 rings are de-tected at much lower frequency in cells lacking Myp2but dots appear more frequently, indicating either thatthe ring is improperly formed or that it subsequently

Fig. 6. Genetic interactions between Myo2 and Myp2 with actinand Cdc7. a: myo2-E1 and myp2D show synthetic lethality with cps8-

(a mutation in the actin gene act11). All three parental strains, butnot the double mutants, form colonies at the semi-permissive temper-

ature (31°C). b: myo2-E1 and myp2D also show synthetic lethalitywith cdc7-24 at 29°C. Calcofluor staining reveals that whereas myp2Dcdc7-24 forms complete septa (c) in the myo2-E1 cdc7-24 strain septafrequently initiate but progress no further (d). Bar 5 10 mm.


collapses if Myp2 is not present (Fig. 5; Mulvihill et al.,1999). Finally, the absence of Myp2 function sup-presses the inhibition of cytokinesis normally associ-ated with Myo2 overexpression (data not shown).Taken together, these results may indicate that Myo2and Myp2 are physically associated in the CAR. Theyalso suggest that Myo2 is the major myosin involved incytokinesis but that the fidelity of Myo2 function isincreased by the presence of Myp2 (Fig. 4).

Myo2 and Myp2 Are Co-RegulatedMyp2 and Myo2 both localise to a ring at the cell

equator (Bezanilla et al., 1997; Kitayama et al., 1997;see above) and both show a strong interaction with theactin mutant cps8- (Motegi et al., 1997; Mulvihill et al.,1999; Fig. 6a), implying that they are part of the samesupramolecular structure, the CAR. Both myo2D andmyp2D strains show a strong genetic interaction withcdc7- (May et al., 1997; Fig. 6b), providing the firstindication that Myp2 and Myo2 are (1) regulated by thesame pathway and (2) that this pathway is the sameone that regulates septum formation. Interestingly,while the myp2D cdc7-24 and myo2-E1 cdc7-24 doublemutants both form aberrant septa at the semi-permis-sive temperature, these are morphologically distinct.In the myp2D cdc7-24 strain, septa span the cell diam-eter whereas in myo2-E1 cdc7-24 septa are frequentlyseen to initiate but to progress no further (Fig. 6c,d). Tofurther explore the relationship of Myo2 and Myp2with the Cdc7 pathway, we compared the effect ofoverexpressing Cdc7 or its activator Spg1 in wild type,myo2-E1 and myp2D strains. Each gene was intro-duced separately into each strain under the control ofthe thiamine repressible nmt41 promoter and cellsscored for the presence of septa 24 hours following theremoval of thiamine from the growth medium. ForSpg1, which is the more potent inducer of cytokinesis,84% of wild type cells had septa; 29% had a singleseptum and 55% more than one (up to 6; Fig. 7a). Inmyo2-E1 and myp2D the number of septum-containingcells was reduced by about 25% but the number con-taining multiple septa was reduced to a much greaterextent. Hence, when Myo2 function is compromised orin the absence of Myp2, the efficiency of septationdriven by Spg1 overexpression is reduced. Again, theappearance of the septa formed in the two myosinmutants is distinct (Fig. 7c,d).

To try to confirm these findings using a differentexperimental approach, we constructed the double mu-tants myo2-E1 cdc16-116 and myp2Dcdc16-116. cdc161

is required to turn off cytokinesis (Fankhauser et al.,1993) and the cdc16-116 mutant forms multiple, un-cleaved septa at the restrictive temperature (Minet etal., 1979). Septum formation was scored after 5 hoursat the restrictive temperature as shown in Figure 8a,b.This experiment revealed little difference between

Fig. 7. Efficiency and accuracy of septation driven by Spg1 over-expression is reduced in myosin mutants. a: Septation index mea-sured after 24 hours of Spg1 production; closed bars 5 wild type,shaded bars 5 myp2D, open bars 5 myo2-E1. b–d: Calcofluor stainingto reveal the morphology of septa in the three strains: (b) wild type, (c)myp2D, (d) myo2-E1. Arrows denote aberrant septa. Bar 5 10 mm.


myp2D cdc16-116 and cdc16-116 in a wild type geneticbackground but it did reveal a major difference in thecase of myo2-E1 cdc16-116, which showed a markedreduction in the initiation of multiple septa. Onceagain, the integrity of septum formation was affected toa different degree in the two myosin mutant strains(Fig. 8d,e).

DISCUSSIONAs in higher eukaryotes, cytokinesis in fungi in-

volves the assembly of a ring of actin at the incipientdivision site (Alfa and Hyams, 1990; Butt and Heath,1988; Kanbe et al., 1989; Kilmartin and Adams, 1984;Marks and Hyams, 1985; Momany and Hamer, 1997)despite the fact that these cells are enclosed within arigid cell wall. As in higher eukaryotes, the recruit-

ment of actin to the cell equator for CAR formation istightly coupled to the assembly of the mitotic spindle,despite the fact that mitosis takes place within anintact nuclear envelope. Thus, unlikely as this mayhave once seemed, the study of cytokinesis in simpleorganisms such as yeasts may well offer significantinsights into the molecular mechanisms of cytokinesisin more complex cells. What yeasts bring to the study ofcytokinesis is a genetic approach in which cytologicalinvestigation of mutant phenotypes can be correlatedwith the function of individual proteins. In fissionyeast, this has resulted in a list of proteins known to beinvolved in the timing of CAR assembly and its place-ment in the cell that has grown steadily over past 3 or4 years (Le Goff et al., 1999). Components of the CARalso continue to be identified and characterised and

Fig. 8. Efficiency and accuracy of septation driven in cdc16-116 isreduced in myosin mutants. a: Septation index measured 5 hoursafter shift of cdc16-116 cells to 36°C. Closed bars 5 cdc16-116, shadedbars 5 cdc16-116 myp2D, open bars 5 cdc16-116 myo2-E1. b: The

myosin mutants contain a higher proportion of aberrant septa. c–e:Septum morphology in cdc16-116 (c), myp2D cdc16-116 (d), andmyo2-E1 cdc16-116 (e). Bar 5 10 mm.


these have included two somewhat unusual type IImyosins (May et al., 1998). As originally proposed byMotegi et al. (1997), Myp2 acts as a stabilising factorfor the Myo2 in the CAR although why fission yeastrequires two cytokinetic myosin II’s when both buddingyeast (Bi et al., 1998; Lippincott and Li, 1998) andDictyostelium (Warrick et al., 1986; DeLozanne andSpudich, 1987) executes cytokinesis with just one isstill not clear. The answer may lie in the unusual tailstructure of the yeast myosin II’s (May et al., 1998) andit will be interesting to see whether Aspergillus, an-other Ascomycete in which the process of septation canbe dissected genetically (Harris et al, 1994; Wolkow etal., 1996), contain similar “unconventional” conven-tional myosins.

Cytokinesis in fission yeast involves the coordinateregulation of two distinct events: the formation andsubsequent contraction of the CAR and the redirectionof the growth machinery from the cell poles to theequator for the deposition of the septum. Septum for-mation involves a signalling pathway that includes theCdc7 protein kinase (Le Goff et al., 1999). Mutants inboth myo21 and myp21 show a genetic interaction withcdc71, suggesting that CAR formation is regulated bythe same pathway. Consistent with this, the efficiencyof septation driven either by the overproduction ofSpg1 (an activator of Cdc7; Schmidt et al., 1997) or bythe inactivation of Cdc16 (an inhibitor of Cdc7;

Fankhauser et al., 1993; Minet et al., 1979) is reducedin the two myosin mutant backgrounds, albeit to dif-ferent extents. In the absence of Myp2, the number ofsepta formed is similar to that seen in wild type cellsalthough these are often structurally aberrant. In thepresence of a functionally compromised form of Myo2,septa are initiated but their formation is aborted at anearly step. We interpret these observations as indicat-ing that the two myosin II’s contribute to temporallydistinct steps in CAR function as summarised diagram-matically in Figure 9. The model assumes that Myo2 iscentral to the initiation of CAR formation, an eventthat is dependent upon the presence of the Myo2 lightchain Cdc4 (Naqvi et al., 1999). Cells lacking Myo2 failto cytokinese and form a dispersed actin ring(Kitayama et al.,1997; May et al., 1997). By contrast,cells lacking Myp2 form a normal actin ring and formsepta, although these are not always functional. ThusMyp2 is involved in some later step, possibly the com-pletion of CAR constriction. This function is dispens-able under normal growth conditions but may be calledon when cells are exposed to stress. One way to test thismodel would be to create a strain that has been engi-neered to contain both myosins fused to different fluo-rescent markers so that their behaviour can be ana-lyzed by high-resolution, real-time microscopy in a sin-gle cell. Given the pace at which this field is advancing,this may not be too far away.

Fig. 9. Model depicting the possible relationship ofthe two fission yeast myosin II’s to each other and tothe Cdc7 pathway. The dashed arrows between Cdc7and Myo2 indicate that these interactions await bio-chemical confirmation.


ACKNOWLEDGMENTSWe thank Tom Pollard, Magdalena Bezanilla, Mo-

han Balasubramanian, Tom Chappell, and ViestursSimanis for strains and plasmids, Vasanti Amin fortechnical assistance, and Yannick Gachet for adviceand encouragement.

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Cytokinesis in fission yeast: A myosinpas de deux