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The Art of Choreographing Asymmetric

Rong Li1,2,* 1Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA 2Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2013.05.003

Asymmetric cell division (ACD), a mechanism for cell-type diversification in both prokaryotes and eukaryotes, is accomplished through highly coordinated cell-fate segregation, genome partitioning, and cell division. Whereas important paradigms have arisen from the study of animal embryonic divisions, the strategies for choreographing the dynamic subprocesses are, in fact, highly varied. This review examines divergent mech- anisms of ACD across different kingdoms. Examples discussed show that there is no obligatory hierarchy among the dynamic events and that asymmetry can emerge from each event, but cell polarization more often occurs as the initial instructive process for patterning ACD especially in the multicellular context.

Asymmetric cell division (ACD) is the process by which one cell such as mammalian oocytes or erythroblasts, ACD succeeds divides to yield two cells of distinct fate, function, and, often- in random orientations when observed in vitro away from their times, size (Figure 1A). ACD has long been appreciated as an natural context, even though the cell polarity that directs ACD important developmental mechanism for the generation of in vivo may be influenced by the cell’s environment. These phe- diverse cell lineages from a single fertilized egg and for its role nomena underscore the principle that ACD, like most morphoge- in the self-renewal and differentiation of stem cells (Gallagher netic processes, is fundamentally self-organizing, and evolution and Smith, 1997; Inaba and Yamashita, 2012; Knoblich, 1997). acts on this capacity to bring about innovation in developmental ACD also occurs in the development and physiology of uni- patterns and responses to changing environments. cellular organisms ranging from bacterial species to yeasts In eukaryotic cells ranging from yeast to plants to animal cell and flagellates (Bi and Park, 2012; Jacobs and Shapiro, 1998; types, Rho family GTPases are widely employed in regulating Rotureau et al., 2012; Shapiro et al., 2002). In these organisms, cell polarity through their highly controlled switching between ACD not only contributes to the production of subpopulations of the GTP- and GDP-bound forms and the ability of the active cells with distinct behavior but also underlies replicative aging GTP-bound form to modulate the activity of a variety of down- as a means of maintaining the immortality of the mitotically stream effectors regulating intracellular structural reorganization proliferating population (Macara and Mili, 2008). In addition, (Craddock et al., 2012; Jaffe and Hall, 2005; Li and Gundersen, some of the specialized cell-differentiation programs unload a 2008). In turn, downstream pathways modulate the upstream large portion of surplus nuclear genome or through regulation through positive feedback loops that help to localize ACD-like processes (Li, 2007). The purpose of this article is or activate the GTPases and some of the effector molecules in not to provide a detailed review of ACD mechanisms associated specific cortical domains of the cell. Emerging results show with any of the individually well-studied experimental models that small GTPases may also be key regulators of cell polarity but to more broadly sample how diverse organisms or cell types in certain bacteria (Kaimer et al., 2012). A recent study reported accomplish a set of highly coordinated subprocesses with their that cell polarity associated with the motility of the bacterium unique logic. Myxococcus xanthus is regulated by two Ras-type GTPases Irrespective of context and purpose, successful ACD requires facilitated by a bacterial cytoskeletal polymer system (Bulyha accurate spatial coordination of three highly dynamic processes: et al., 2013). the segregation of cell-fate determinants, chromosome segrega- Both symmetric and asymmetric cell divisions must partition tion (or, in the special case of erythrocyte enucleation, elimina- the genome in desired proportions (most frequently with equal tion), and cell division (Figure 1B). Cell polarity, a property of segregation into daughter cells). This requires cytokinesis to be asymmetric cellular organization, defines two opposing sides positioned appropriately relative to the axis of chromosome of the cell that are biochemically and structurally distinct (Li segregation. The structural requirement and spatiotemporal and Gundersen, 2008; Macara and Mili, 2008). Cell-fate determi- control of cytokinesis have been extensively studied and are nants are segregated differentially to these poles through a vari- best understood for mitotically dividing cells of animals and ety of mechanisms, and polarized cortical components often yeast (Green et al., 2012; Pollard, 2010). One of the key mecha- instruct the positioning and orientation of the spindle and, conse- nisms in animal cells, termed equatorial stimulation, entails a Rho quently, the plane of cell division. During multicellular develop- GTPase-dependent signal emanated from the midzone region of ment, establishing cell polarity along a stereotypical orientation the elongating anaphase spindle for the induction of the assem- is often the first critical step, and it helps to fulfill ACD’s role in bly of a cytokinetic furrow driven by actomyosin contraction (Jor- patterning the developing . In unicellular organisms, dan and Canman, 2012; White and Glotzer, 2012). A recent study ACD is a cell-autonomous process that relies on organisms’ found that a component of the midzone complex, called self-organizing capacity. However, in certain animal cell types, MgcRacGAP, required for both Rho activation (Loria et al.,

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Figure 1. Fundamental Requirements of ACD (A) Simple schematics of symmetric versus asymmetric cell division. The former produces two identical daughter cells that are usually of the same identity as the progenitor cell; the latter produces two cells of different identities that may or may not be the same as the progenitor cell. (B) Dynamic events (boxed letters) that must be tightly coordinated during ACD. Dashed arrows represent possible instructive processes linking the different ACD events in the examples discussed in this review. In most systems, cell polarity plays an overarching role in the spatial organization of ACD.

tion, and tethering of the origins of DNA replication and/or bulk transport of chromo- somes (Wang et al., 2013). Cell division is accomplished by a ring of the tubulin-like FtsZ protein, whose mechanisms of posi- tioning may defer dramatically between sym- metric versus asymmetric cell divisions (Bara´ k and Wilkinson, 2007). As discussed below, structural mechanisms coordinating cell division and chromosome segregation 2012) and the inhibition of Rac1-mediated cell spreading (Bastos may, to a large degree, constrain the design of ACD in diverse et al., 2012), contains a phospholipid-binding domain that inter- organisms. acts physically with the furrow plasma membrane (Le- komtsev et al., 2012). Regulation by the spindle midzone ensures The Paradigm: Mitotic ACD during Animal Development that the cell cleaves persistently through a plane equidistant to Current paradigms of ACD arose from the study of animal devel- the segregated masses of chromosome, and, thus, equal parti- opment, most importantly the study of early zygotic divisions in tioning of the genome occurs between daughter cells. However, the and asymmetric divisions during ACD of mitotic animal cells, a frequent additional feature in the neuroblast lineage. Because is the production of two cells of different sizes. This can be these have been extensively reviewed in recent years (Morin accomplished either by asymmetric positioning of the entire and Bellaı¨che, 2011; Munro and Bowerman, 2009; Prehoda, spindle or by having an asymmetric spindle with arms of unequal 2009; Siller and Doe, 2009), the following discussion will reiterate lengths (Siller and Doe, 2009). the general principles while highlighting the newest advances in In nonanimal organisms, such as fungi and plants, different these two well-studied systems. These ACDs share the common mechanisms underlie cleavage furrow positioning because of scheme that cell polarity, spindle orientation and positioning, distinct morphological features of their mitoses. For example, and cell division are coordinated in a clear hierarchical manner. most species of yeast undergo ‘‘closed mitosis,’’ whereby the Cell polarity, pre-established prior to mitosis, not only segre- spindle assembles and operates within an intact nuclear enve- gates fate determinants but also dictates the orientation and lope, presenting a barrier for direct communication between position of the mitotic spindle through the interactions of astral the spindle and the cortex. In fission yeast cells, which divide microtubules with polarized cortical components (Figure 2A). In from the middle of the long cell axis, the position of the nucleus turn, the spindle specifies the position of the cleave plane. determines the placement of the cytokinetic ring (Bathe and ACD is a recurrent process in the generation of diverse cell Chang, 2010; Rincon and Paoletti, 2012). A balance of microtu- lineages during C. elegans embryonic development, starting at bule-length-dependent forces places the interphase nucleus the very first zygotic division (Munro and Bowerman, 2009). and, hence, the future division site at the center of the rod- Sperm entry initiates the dynamic events that lead to symmetry shape cell (Daga et al., 2006; Tolic-Nørrelykke et al., 2005; breaking and spatially orients the establishment of an anterior- Tran et al., 2001). Budding yeast cells specify their division posterior (A-P) polarity with opposing cortical domains marked site even earlier, which is concomitant with cell polarization by two complementary sets of partitioning (PAR) proteins. Along (Bi and Park, 2012). In most plant cells, the division site is a plane orthogonal to the A-P axis, asymmetric division gener- also determined before mitosis by a transient microtubule- ates two cells destined for distinct developmental fates: the containing cortical ring called the preprophase band (PPB) posterior P1 cell gives rise to the germline and some somatic (Rasmussen et al., 2011). Although short-lived, the PPB leaves lineages, whereas the anterior AB cell only generates somatic behind a molecular memory that eventually determines the site cells (Figure 2B). The posterior germ cell fate correlates with, where an expanding cell division structure called the phragmo- though does not strictly require, the concentration of the RNA- plast fuses with the plasma membrane during telophase. containing germ granules (P granules) in the posterior cytoplasm Finally, bacterial cells segregate their chromosomes through of the (Gallo et al., 2010; Updike and Strome, 2010). The spatially ordered condensation of replicated DNA, transloca- A-P polarity constitutes a mechanism for preferential dissolution

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Figure 2. ACD in Mitotic Animal Cells and Erythroblast Enucleation (A) The common scheme shared in mitotic ACD during animal development is the key role for cell polarity, established after an environmental cue, in instructing the position and orientation of the spindle. The spindle midzone complex (small green square) determines the site of cell division. (B and C) ACD of C. elegans zygote (B) and Drosophila embryonic neuronblast (C). Color schemes are consistent with the font colors in (A) GMC, ganglion mother cell; Mira, Miranda. (D) Erythroblast enucleation. Presently, it is unclear if there are initial markers of cell polarity other than the asymmetrically located MTOC. or condensation of P granules on the anterior or posterior side symmetry breaking by protecting PAR-2 at the posterior cortex of the first cleavage plane, respectively (Brangwynne et al., against inhibitory phosphorylation by aPKC, a partner of PAR-3 2009). and PAR-6 (Motegi et al., 2011). Early genetic analysis uncovered key molecular regulators The cortical polarity marked by anterior and posterior PAR required for A-P polarity establishment, whereas studies in proteins is instrumental for the orientation and positioning of recent years offered mechanistic insights into the mechanism the spindle during the first zygotic division (Morin and Bellaı¨che, of symmetry breaking and the role of the sperm in 2011; Siller and Doe, 2009). Spindle orientation and positioning the induction and orientation of A-P polarity. The prevailing occurs in two distinct steps before spindle formation and during model posits that the sperm centrosome triggers an asymmetric anaphase, respectively, but both processes depend on cyto- contraction of the cortical actomyosin cytoskeleton, which plasmic dynein acting on astral microtubules (Grill and Hyman, drives a cortical flow that transports anterior PAR proteins, 2005). First, the spindle assumes a central position, but, during such as PAR-3 and PAR-6, toward the anterior pole (Bienkowska anaphase, a net movement of the elongating spindle toward and Cowan, 2012; Goehring et al., 2011; Munro and Bowerman, the posterior pole sets up an asymmetric cleavage plane, gener- 2009; Zonies et al., 2010). The advective transport-generated ating a smaller posterior daughter (P1 cells). Although the signif- transient PAR-3 and PAR-6 asymmetry is enhanced by a dou- icance of this size asymmetry is unclear, mechanistic dissection ble-negative feedback loop consisting of mutually inhibitory in- of this process has illuminated the understanding of how cortical teractions between anterior and posterior PAR proteins, polarity instructs the spatial control of ACD. Elegant studies that enabling the establishment of stably opposed anterior and pos- involved laser ablation, quantitative imaging, or modeling re- terior domains (Goehring et al., 2011). In addition to the actomy- vealed a polarized distribution of forces favoring the posterior- osin-based transport system, sperm centrosome-associated bound movement mediated by dynamic astral microtubules microtubules represent a second mechanism that could trigger making cortical contacts (Grill et al., 2001; Kozlowski et al.,

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2007). An unexpected molecular system that emerged as a key The anaphase spindle asymmetry correlates with a larger regulator of this force asymmetry is the heterotrimeric G protein centrosome with a higher microtubule-nucleating capacity on and its unconventional effectors GPR-1 and GPR-2 (Morin and the apical side. Ga-Pins and the apical polarity proteins repre- Bellaı¨che, 2011; Siller and Doe, 2009). The activity of the G pro- sent two redundant pathways regulating this spindle asymmetry tein in this regulatory role does not rely on a typical upstream (Cai et al., 2003). Asymmetric anaphase spindle morphogenesis transmembrane receptor but lies, strangely, in the GDP (not was also observed in C. elegans Q neuroblasts, migrating GTP)-bound Ga subunit. GPR-1 and GPR-2 proteins are en- progenitor cells that undergo ACD (Ou et al., 2010). In this sys- riched at the posterior cortex in a PAR-2- and PAR-3-dependent tem, myosin II-driven cortical contraction ‘‘squeezes’’ the half manner and, upon binding to GaGDP, enhance dynein motor ac- of the cell on one side of the central spindle and expands the tivity in favor of posterior-directed spindle movement. other half, resulting in a more dramatic extension of the spindle ACD of Drosophila neuroblasts represents another pioneering arm in the latter, hence a small and a large cell are formed after model that has uncovered the ground rules and key regulatory cell division. molecules enabling stem cells to simultaneously fulfill the paradoxical tasks of self-renewal and differentiation (Doe, An Interphase Adaptation of Mitotic ACD: Erythrocyte 2008; Prehoda, 2009). Neuroblasts are transient populations of Enucleation -like progenitor cells that give rise to neurons and glial The processes discussed above share the fundamental feature cells of the embryo and larvae. Because some differences exist of cell polarity being the central organizer of ACD and guiding between the two sources of neuroblasts, and for the sake of the segregation of cell-fate determinants and spindle orientation clarity, the following discussion solely refers to embryonic neu- and positioning. This scheme of ACD is also used in certain roblasts. During neurogenesis, neuroblasts delaminate to the mammalian cell types to eliminate a major portion of the cell basal surface of the neuroectoderm and undergo ACD in order during differentiation. A compelling example is erythroblast to produce a neuroblast and a ganglion mother cell destined enucleation, during which an interphase cell ejects its nucleus, to differentiate into a neuron (Figure 2C). The distinct daughter giving rise to an anucleate reticulocyte (Ji et al., 2011). Erythro- cell fates are prepatterned prior to cell division through the local- blast enucleation has similar structural requirements as mitotic ization of several proteins that either promote the ganglion cell cytokinesis; i.e., an actomysin-based contractile ring drives mother cell fate or antagonize neuroblast identity to the basal a constriction at the base of the extruding nucleus (Ji et al., 2008; cortex of the delaminated neuroblasts opposite the side con- Konstantinidis et al., 2012; Koury et al., 1989; Ubukawa et al., tacting the neuroepithelium (the apical side). Cell polarity estab- 2012; Wang et al., 2012), and endocytic membrane trafficking lished through the PAR-3 and PAR-6 and aPKC protein network possibly supplies the membrane in order to accommodate the regulated by the small GTPase CDC42 at the apical cortex is increasing surface area (Keerthivasan et al., 2010; Simpson required for the exclusion of the ganglion mother cell fate pro- and Kling, 1967). However, unlike typical cytokinesis, enucle- teins from the apical side of the mitotic neuroblast. One of the ation occurs in interphase, serving a purpose of genome elimina- mechanisms involves the phosphorylation of a scaffold protein, tion rather than genome transmission. Miranda, by aPKC and, hereby, prevents cortical concentration To preserve the majority of erythroblast cytoplasm in order to of Miranda and its bound fate proteins (Atwood and Prehoda, support reticulocyte development and function, the nucleus un- 2009). Spindle positioning is again controlled by apical PAR pro- dergoes condensation and protrudes tightly against the plasma teins through interaction with inscuteable (Insc), which interacts membrane on one side of the cell, and membrane components with partner of inscuteable (Pins)—the fly version of the worm to be eliminated or destined for the reticulocyte are sorted in GPR-1 and GPR-2 (Morin and Bellaı¨che, 2011; Siller and Doe, opposite directions (Ji et al., 2011). Such reciprocal segregation 2009). The network of interactions among apical polarity pro- of major cellular components is clearly indicative of an underlying teins, Insc, Pins, and the membrane-anchored Ga activate the cell polarity being established early during enucleation. Cyto- dynein motor through NuMA and Lis1. In the first cycle of neuro- skeletal elements are also organized in a polarized manner blast ACD, this force rotates the metaphase spindle, initially (Figure 2D). F- accumulates preferentially on the cortex assembled parallel to the neuroectoderm, so that it aligns with and in the cytosol on the cytoplasm side of the erythroblast the apical-basal axis (Kaltschmidt et al., 2000). In subsequent and also forms a contractile ring that contains myosin II demar- cycles, spindle alignment may be achieved by maintaining a cating the boundary between the two incipient daughters (Ji dominant centrosome at the apical cortex during bipolar spindle et al., 2008; Konstantinidis et al., 2012; Koury et al., 1989; Ubu- formation (Rebollo et al., 2009). kawa et al., 2012; Wang et al., 2012). The inhibition of Rac Whereas the above force-generating system helps orient the GTPase prevents contractile ring assembly and disrupts actin spindle along the apical-basal axis, neuroblast division also pro- distribution asymmetry, but the nucleus still migrates to one duces daughter cells of different sizes that result from a spindle side of the elongated erythroblast, indicating the persistence of asymmetry developed during anaphase (Kaltschmidt et al., cell polarity (Ji et al., 2008; Konstantinidis et al., 2012). Microtu- 2000). But, in contrast to asymmetric displacement of a symmet- bules, on the other hand, appear to have a more prominent role in ric spindle in the C. elegans zygote, the neuroblast spindle asym- cell polarization and asymmetric nuclear positioning. Prior to nu- metry lies in the anaphase spindle itself; i.e., the spindle arm on cleus movement, microtubules form a basket with the g-tubulin- the apical side of the central spindle region is longer than the containing microtubule organizing center (MTOC) on the bottom opposite side, effectively shifting the cleavage plane toward of the basket (Konstantinidis et al., 2012; Koury et al., 1989; the basal cortex, thus producing a ganglion mother cell consid- Wang et al., 2012). Cell elongation and nuclear extrusion occur erably smaller than the sibling neuroblast (Figures 2B and 2C). as the microtubule basket remains at the opposite end with the

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Figure 3. ACD in Budding Yeast and Plant SMCs The common scheme shared between these two processes is that cell polarity, oriented according to external cues (bud scar in the case of yeast), promptly specifies the site of cell division before spindle assembly. In yeast, cell polarity and the predetermined division site jointly control the posi- tioning of the spindle enclosed in the nucleus. The purple circles in the nucleus represent extra recom- binant DNA circles that accumulate in aging mother cells. In plant SMCs, cell polarity dictates an asym- metric positioning of the nucleus first and, subse- quently, dictates the position and orientation of the spindle. GC, guard cells arising from a symmetric division of the GMC; SC, subsidiary cell.

intracellular vacuole. Contractile ring for- mation during enucleation requires Rac and not Rho, which directly or indirectly ac- tivates the formin family actin nucleator mDia2 (Ji et al., 2008). Clearly, many mech- anistic details of erythroblast enucleation remain to be flushed out, but the emerging picture is a ‘‘tinkered’’ cytokinesis machin- ery that relies on an intrinsic cytoskeletal MTOC sandwiched in the tight space between the microtubules asymmetry and employs similar, but not identical, structural and the polar cortex (Figure 2D). Assuming that microtubules and regulatory elements to those accomplishing cell division are oriented with their minus ends at the MTOC and plus ends during mitosis. out around the nuclear surface, a plus-end-directed microtubule motor could slide apart the microtubule basket and the nucleus Variation on the Polarity Rule: ACD in Budding Yeast and to opposite sides of the cells. Supporting this model, micro- Plant Stomatal Development tubule inhibition prevents the establishment of an off-center Walled cells of yeast or plants have a different take on the logic nuclear position and reduces the efficiency of enucleation (Kon- of ACD. A common feature exhibited by these systems is stantinidis et al., 2012). In addition to a possible mechanical role that, although cell polarity still provides the principal guidance, for moving the nucleus, microtubules are also required for the specific morphological features of these mitoses may have influ- activation of PI3 kinase, which produces PtdIns(3,4)P2 and enced how the downstream events are ordered. In the two ex- PtdIns(3,4,5)P3 on the reticulocyte side of the plasma membrane amples discussed below, an immediate decision following cell (Wang et al., 2012). Blocking PI3 kinase activity delays and de- polarization is the placement of the future site of cell division stabilizes the asymmetry in nuclear position and actin distribu- well before mitosis. The spindle is oriented in line with cell polar- tion. ity and positioned in accordance to the predetermined cell divi- If microtubules drive erythroblast polarization, then the first sion site (Figure 3A). polarity cue may be the position of the erythroblast MTOC, which ACD of Budding Yeast nucleates a polarized microtubule array whose plus ends extend The yeast Saccharomyces cerevisiae cells achieve mitotic prolif- toward the nucleus and could stimulate the formation of the eration by forming a bud through polarized growth (Bi and Park, actomyosin ring. An interesting parallel was reported in mitotic 2012; Pruyne and Bretscher, 2000). At the G1-to-S transition, a HeLa cells, where the inhibition of Eg5 kinesin leads to the forma- mother yeast cell previously undergoing isotropic growth polar- tion of a monopolar spindle that resembles the aforementioned izes for the specification of an incipient bud site at one pole of the microtubule basket and a ‘‘pear-like’’ cell-shape distortion with cell. Continued polarized growth toward this site, coupled with apparent similarity to that of an enucleating erythroblast (Hu the assembly of a nonexpanding bud neck, leads to the emer- et al., 2008). More remarkably, the plus ends of the microtubules gence and enlargement of a bud into which chromosomes are induce the formation of an actomyosin ring by recruiting proteins segregated. Cytokinesis, which involves an actomyosin contrac- that normally localize to the central spindle and stimulate the tile ring, local membrane deposition, and septal wall synthesis, cleavage furrow. Survivin, one of the chromosome passenger proceeds at the bud neck. Less known is the fact that each of complex (CPC) components that localizes to the central spindle these cell divisions is asymmetric (Figure 3B). Haploid yeast cells and regulates cytokinesis (Carmena et al., 2012), was found to have two different mating types. After each division, the mother localize to the region of constriction in erythroblasts and is cell switches her mating type by means of HO-endonuclease- important for enucleation (Keerthivasan et al., 2012). However, mediated recombination while the bud cell maintains the original instead of forming CPC, survivin in erythroblasts binds clathrin mating type of the mother (Haber, 2012). This cell-fate asymme- and Esp15 and promotes enucleation by regulating the formation try is determined by the localization of the ASH1 messenger

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RNA, encoding the transcriptional repressor of HO, in the bud phase spindle and nucleus closely at the bud neck (Kusch prior to cell division (Long et al., 1997). The mother and the et al., 2002; Segal et al., 2000). Finally, during anaphase, the bud also defer in replicative age—a mother cell undergoes repli- SPB destined for the bud is pulled across the bud neck as a cative aging each time she gives birth to a bud and has a finite result of microtubule sliding against the bud cortex by the replicative life span of 25 divisions, whereas the bud cell is a minus-end-directed motor dynein while the other SPB is main- newborn with full replicative potential (Henderson and Gottsch- tained in the mother most likely as a result of both spindle elon- ling, 2008). Aging determinants are segregated asymmetrically gation and dynein action at the mother cortex (Markus et al., during each division; i.e. toxic wastes are retained by the mother 2012). whereas some newly synthesized beneficial components are An implicit requirement with the above mechanism of spindle preferentially deposited in the bud (Aguilaniu et al., 2003; Elda- positioning and orientation is that the two SPBs must experi- kak et al., 2010; Sinclair and Guarente, 1997). Thus, the buds ence different forces such that, when one SPB is pulled toward are, in essence, the ‘‘stem cells’’ of a yeast population that retain the bud, the other stays behind or is actively pulled toward the the original sexual identity and endow the population replicative mother pole. This requirement is satisfied through a biochem- immortality. In fact, certain features of yeast ACD, such as asym- ical asymmetry between the two SPBs. A bipolar spindle has metric centrosome inheritance and the existence of a checkpoint a new and an old SPB. The old SPB is always destined for mechanism to ensure correct spindle orientation, have also been the bud (Pereira et al., 2001). Consistent with this fate, Kar9 observed in the Drosophila male germline stem cell divisions only localizes asymmetrically to the old SPB and then gets (Pereira and Yamashita, 2011). transported along its astral microtubules to the plus ends for Hallmarks of yeast cell polarity include the localization of more the mediation of cortical pulling (Liakopoulos et al., 2003; Mae- than 100 different proteins, most importantly the Cdc42 kawa et al., 2003). Dynein heavy chain follows a similar localiza- GTPase, at the incipient bud site and bud cortex, and oriented tion pattern (Grava et al., 2006; Lee et al., 2005). These asym- actin cables that serve as ‘‘highways’’ for polarized transport metries determine that the old SPB is pulled toward the bud of membrane, RNA, and organelle materials. The establishment tip while the new SPB stays behind. In addition, there exists of cell polarity orchestrated by Cdc42 and other Rho family an intricate checkpoint mechanism, termed spindle orientation GTPases has been studied extensively and reviewed recently checkpoint, which delays mitotic exit and cytokinesis if the (Park and Bi, 2007; Slaughter et al., 2009). An immediate conse- leading SPB fails to traverse the bud neck (Caydasi et al., quence of cell polarization is the specification of the future site 2010). The proper operation of this checkpoint also relies on of cell division—the bud neck. A key scaffold of the bud neck the asymmetric localization of several signaling molecules to are the septins, filamentous structures consisting of four or either the old or the new SPB. five different septin subunits (McMurray and Thorner, 2009). How does the cell distinguish between the old and the new The septin proteins localize to the incipient bud site in a SPB? One inherent difference is that the old SPB, on virtue of Cdc42-dependent manner and mature into the septin ring as its longer existence and greater maturity, nucleates astral micro- the bud emerges. The septin ring helps lay down chitin for the tubules more often and earlier than the new SPB. When nocoda- formation of a rigid bud neck and localizes key components of zole was used to disrupt all existing microtubules and then the cytokinetic machinery, such as myosin II, as early as S washed out in order to allow mitosis resumption, one of the phase (Bi et al., 1998; DeMarini et al., 1997; Lippincott and Li, SPBs would become the leading pole and the biochemical 1998). The septins also serves as a barrier for membrane diffu- asymmetry would develop accordingly (Pereira et al., 2001; sion that helps maintain asymmetric partitioning of cellular com- Seshan and Amon, 2004). In this case, it was roughly a 50-50 ponents (Luedeke et al., 2005; Orlando et al., 2011; Takizawa chance for the old versus new pole to be bud bound, suggesting et al., 2000). that symmetry breaking occurred spontaneously and randomly. The yeast spindle is aligned in accordance with the axis of A positive feedback loop between the pulling force and the cell polarity and positioned in reference to the bud neck loading of the force producing machinery possibly tips the bal- (Figure 3B). Even prior to spindle assembly, astral microtubules ance between the two SPBs. emanating from a single spindle pole body (SPB) initiate inter- ACD in Stomatal Development of Grass Plants action with cortical components at the tip of the emerging ACD is a highly prevalent mechanism for embryonic patterning bud (Adames and Cooper, 2000; Segal et al., 2002). After bipo- and the development of tissue architecture in plants (Abrash lar spindle formation, astral microtubules from the old SPB are and Bergmann, 2009; Rasmussen et al., 2011). ACD has been guided by a complex of plus-end-associated proteins Kar9 and recognized in such processes as early embryonic divisions, Bim1, which links the microtubule plus end to Myo2, a type V root formation, and pollen development, but the of myosin that moves along oriented actin cables (Pearson and these ACDs remains largely unknown. A relatively well-charac- Bloom, 2004). Once transported to the bud tip, astral microtu- terized case is subsidiary mother cell (SMC) division (Pillitteri bule plus ends are captured by Bud6, a component of the polar and Torii, 2012), although this mechanism of ACD may not be cortex. A coupling of dynamic capture and plus end depolymer- general to most plant cells. Stomata are structures on the leaves ization catalyzed by Kip3, a kinesin 8, generates a pulling force for gas exchange. A stomatal complex consists of a pair of guard orienting the spindle along the mother bud axis (Gupta et al., cells, each supported by a subsidiary cell, which control the sto- 2006; Pearson and Bloom, 2004; Su et al., 2011; Ten Hoopen matal pore. In grasses such as maize, stomata formation in- et al., 2012). Astral microtubules are also captured by bud- volves a guard mother cell (GMC) for interacting with two neck-bound Bud6 and shortened in a manner dependent on SMCs in neighboring cell files. This interaction induces the two neck-associated kinases. This helps position the preana- SMCs to undergo ACD to each generate a small subsidiary cell

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Figure 4. ACD in Mouse Oocytes Undergoing Meiotic Maturation (A) Asymmetric spindle positioning induces cell polarity and specifies the division site. It is unclear whether specific cell-fate determinants are segregated or whether differential cell fates result from the dramatic daughter cell size difference. (B) The MI spindle undergoes a self-organizing migra- tion toward the cortex and induces cortical polarity, which leads to the activation of cytoplasmic streaming, further promoting spindle movement and helping to maintain the MII spindle at a subcortical location (the MII spindle must undergo a rotation during anaphase). Actomyosin accumulation at the polar cortical domain defines the site of polar body (PB) extrusion.

entry, a bipolar spindle forms at the position of the microtubule basket. Dense bundles of actin connect the spindle pole proximal to the SMC-GMC contact site and help main- tain the proper orientation of the spindle. Although mechanistic details remain elusive, tightly contacting two guard cells produced through a symmetric the emerging framework in this plant ACD is a dominant polarity division of the GMC (Figure 3C). axis oriented with the cue from neighboring cells laying down the The GMC-SMC contact site provides the cue for the establish- ground plan for the mechanical processes of ACD. ment of cell polarity (Figure 3C), marked by the localization of PAN1 and PAN2, two leucine-rich repeat-receptor-like kinases, Chromosomes Leading the Way: Meiotic ACD in and a cortical patch of F-actin (Cartwright et al., 2009; Panteris Mammalian Oocytes et al., 2007; Wick, 1991; Zhang et al., 2012). PAN1 and PAN2 Meiotic cell divisions fulfill the roles of genome recombination act in a partially redundant manner to induce all aspects of and reduction of chromosome complements to produce SMC polarity, and double mutants affecting these proteins haploid gametes. An immature oocyte with a 2N (4C) chromo- strongly perturb ACD. One process downstream of PAN1 and some (DNA) content undergoes two rounds of extremely asym- PAN2 is the assembly of the cortical actin patch, which is depen- metric cell divisions in order to achieve genome reduction. The dent on BRICK1, a component of the WAVE complex that acti- overwhelming size difference between the egg and the polar vates the Arp2/3 complex, a conserved actin regulator that forms body, products of each meiotic division, enables the egg to branched actin networks, and ROP2 and ROP9, two plant Rho maintain the majority of cellular constituents in order to support family GTPases (Frank et al., 2004; Frank et al., 2003; Humphries future embryonic development, whereas the polar body with et al., 2011). ROP proteins physically interact with PAN1 and are scarce cytoplasm is destined for apoptosis. As in mitotic ACD, likely to function analogously to Rac in animal cells, which acti- the size asymmetry correlates with asymmetric positioning of vates the WAVE complex in order to stimulate Arp2/3-mediated the spindle and cell-division site. However, the fact that most actin polymerization (Takenawa and Suetsugu, 2007). These meiotic spindles lack or have only short astral microtubules con- findings outline a potential signaling pathway whereby an asym- strains how spindle positioning may be accomplished. In metric cue from the physical contact between GMCs and SMCs Drosophila and C. elegans oocytes, meiotic spindle positioning is transmitted through the receptor-like PAN1 and PAN2 pro- is largely a result of microtubule-driven nuclear migration to a teins, which recruit Rho type GTPases and promotes polarized subcortical location prior to entry into meiosis I (MI). Polymerizing actin assembly nucleated by the Arp2/3 complex. microtubule plus ends exert a pushing force behind the migrating affecting the above signaling pathway prevent the nucleus in Drosophila oocytes (Zhao et al., 2012), whereas, in proper differentiation of the daughter cell of an SMC division C. elegans oocytes, nuclear movement depends on the microtu- adjacent to a GMC into a subsidiary cell, suggesting that SMC bule motor kinesin I (McNally et al., 2010). polarity is intimately linked with fate asymmetry of the daughter An even less conventional progression of ACD occurs during cells (Gallagher and Smith, 2000). Analogous to the sequence meiotic maturation of mouse oocytes (Li and Albertini, 2013) of events in budding yeast, a PPB forms surrounding the actin (Figure 4A). The prophase I nucleus of an immature oocyte is patch and precisely defines the future site of cell division simul- located away from the cortex and often near the cell center, taneous to the formation of the polar actin patch (Gallagher and where the first meiotic spindle assembles. After chromosome Smith, 2000; Panteris et al., 2006)(Figure 3C). SMC polarity also alignment, the metaphase spindle migrates to a cortical location directs the migration of the nucleus to the actin patch. This (Longo and Chen, 1985). Soon after the leading pole touches the migration is dependent on F-actin and not microtubules, but a cortex, anaphase occurs, followed by the extrusion of the first microtubule basket with its open end terminating at the PPB polar body. Meiosis II (MII) spindle then assembles at a closely helps maintain the nuclear position after migration (Kennard adjacent subcortical site, and the mature oocyte will arrest in and Cleary, 1997; Panteris et al., 2006)(Figure 3C). After mitosis MII metaphase until fertilization, which triggers MII anaphase

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Figure 5. ACD in Sporulating B. subtilis (A) Cell-division site plays a central instructive role for chromosome segregation and cell-fate asym- metry. (B) This bacterial ACD starts with stochastic choice of a polar division site, which then recruits the motor protein for chromosome movement into the fore- spore and produces cell-fate asymmetry due to the transient genetic asymmetry of the SpoIIAB gene, leading to the activation of different sigma factors on the two sides of the septum.

(Figure 4B). In contrast to that occurring in mitotic ACD, where studied ACDs in prokaryotes. Another well-studied bacterial cortical polarity guides spindle positioning, the meiotic chro- ACD is that of Caulobacter crecentus, which, similar to the matin induces all aspects of cortical polarity, a feature of which budding yeast, relies on cell polarity oriented by inherited struc- is a cap-like domain enriched for F-actin surrounded by a ring tural features to orchestrate the subsequent cell division events. of myosin II (Deng et al., 2007; Longo and Chen, 1985; Maro For the purpose of mechanistic contrast, the following discus- et al., 1986). This cortical domain defines the site of polar body sion focuses on the unique mode of ACD in sporulating extrusion. Induction of the cortical actin domain does not require B. subtilis. the chromatin to physically contact the cortex but needs the dis- Sporulation is a response of the bacterium to starvation, pro- tance between the two to be less than 20 mm (compared to an ducing a small spore in order to survive the stress through average oocyte radius of 35 mm) to allow for the activation of the dormancy and leaving a large mother cell to perish. The first Arp2/3 complex (Deng et al., 2007; Yi et al., 2013; Yi et al., 2011). morphological asymmetry in this primitive form of ACD is the Thus, asymmetric spindle and chromosome positioning sets up establishment of an asymmetric septum (bacteria’s cell-division oocyte polarity. Both the spindle and naked chromatin are able site) through an altered structural assembly of the filament-form- to move to the cortex in an actin-dependent manner (Longo ing protein FtsZ (Ben-Yehuda and Losick, 2002). FtsZ is the main and Chen, 1985; Van Blerkom and Bell, 1986). Fmn2, a formin building block of bacteria’s cytokinetic ring that normally forms family actin-nucleating protein, was the first actin regulator found at the cell center with the duplicated chromosomes tethered to be crucial for this process (Dumont et al., 2007; Leader et al., by their origins of replication to opposing poles of rod-shaped 2002). cells (Bara´ k and Wilkinson, 2007; Erickson et al., 2010). Starva- There are currently two models for how actin-based forces tion triggers the sporulation program, which starts with FtsZ break oocyte symmetry by displacing the spindle from the forming a long helix extending across the central portion of the oocyte center to a subcortical location. In an earlier model, a cell, the two ends of which demarcating two potential, but network of cytoplasmic actin filaments nucleated by cortex- competing, sites of asymmetric cell division (Ben-Yehuda and associated Fmn2 contracts due to spindle-pole-associated Losick, 2002)(Figure 5B). Only one of the two division sites is myosin II, and a stochastic force imbalance toward one side pulls eventually used, whereas the other one regresses (Eichenberger the spindle to the cortex (Azoury et al., 2011; Schuh and Ellen- et al., 2001; Pogliano et al., 1999). SpoIIIE, an ATP-dependent berg, 2008). A more recent model is based on the observation DNA-tracking motor protein, localizes to the more advanced, that the migration of the MI spindle or chromosomes occurs in but still only partially closed, septum and initiates the pulling of a biphasic manner (Yi et al., 2013). The first phase resembles a the chromosome toward the side destined to become the fore- random walk driven by Fmn2-nucleated actin polymerization at spore, the spore precursor (Bath et al., 2000; Wu and Errington, the spindle periphery. This initial random motion displaces the 1997). chromosomes just enough to allow the chromatin signal to reach The most remarkable thing about this ACD is the fact that dif- the cortex to activate the Arp2/3 complex. The Arp2/3 complex ferential cell fates do not require pre-established stable cell po- nucleates a dynamic actin network, which drives cytoplasmic larity but, instead, emerge during chromosome segregation as a streaming in a pattern producing a pushing force on the spindle result the transient asymmetry in the copy number of the gene toward the Arp2/3-concentrated cortex (Figure 4B). The Arp2/3- encoding the antisigma factor SpoIIAB (Dworkin and Losick, complex-dependent cytoplasmic streaming also serves to main- 2001)(Figure 5B). A temporary lack of the gene on the forespore tain the MII spindle subcortically in the mature oocyte (Yi et al., side and having two copies on the mother cell side, coupled with 2011). Thus, during ACD in mouse oocyte, meiotic chromo- the instability of the SpoIIAB protein and also, most likely, a bar- somes recruit or activate their own motility machinery in order rier effect of the advanced septum, allows for the preferential to induce cortical polarity and specify the site of cell division. activation of sF only in the forespore, committing it to further dif- ferentiation. sF also induces a paracrine signaling mechanism Turning the Logic Upside Down: ACD during Sporulation that produces sE in the mother cell (Hofmeister et al., 1995; of Bacillus subtilis Karow et al., 1995), solidifying the mother cell fate and causing The self-organizing way of ACD in mouse oocytes may find its the disassembly of the other potential division site. In this way, origin in the remarkable sporulation process of the bacterium the sporulating B. subilis performs ACD through a logical Bacillus subtilis (Bara´ k and Wilkinson, 2007; Horvitz and Hersko- progression opposite of that in mitotic animal cells. Cell-division witz, 1992; Shapiro et al., 2002)(Figure 5), one of the more well- site establishment places the chromosome segregation

446 Developmental Cell 25, June 10, 2013 ª2013 Elsevier Inc. Developmental Cell Review

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