Available online at www.sciencedirect.com

ScienceDirect Control of asymmetric cell division Chantal Roubinet and Clemens Cabernard Asymmetric cell division (ACD) is a mechanism to generate cellular diversity and used by prokaryotes and eukaryotes alike. Stem cells in particular rely on ACD to self-renew the stem cell while simultaneously generating a differentiating sibling. It is well established that the differential partitioning of cell fate determinants in the form of RNA and proteins between sibling cells induces changes in cell behavior and fate. Recently, insight into molecular mechanisms has been gained that could explain how centrosomes and centrosome-associated structures such as histones, chromosomes or the primary cilium, segregate asymmetrically. Similarly, many cell types also generate physical asymmetry in the form of sibling cell size differences. Emerging data suggests that spindle-induced cleavage furrow positioning through regulated spindle placement and spindle geometry is insufficient to explain all occurrence of cell-size asymmetry. Instead, asymmetric membrane extension based on asymmetric Myosin localization and cortical remodeling could be a driving force for the generation of physical asymmetry. Addresses Biozentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland Corresponding author: Cabernard, Clemens ([email protected])

Current Opinion in Cell Biology 2014, 31:84–91 This review comes from a themed issue on Cell cycle, differentiation and disease Edited by Stefano Piccolo and Eduard Batlle For a complete overview see the Issue and the Editorial Available online 28th September 2014

several aspects of asymmetric cell division, such as cell fate determinant segregation and spindle orientation. Many excellent reviews have already been written on this topic [1,3,4,6,7]. Here, we will first discuss new data concerning centrosome asymmetry, biased chromosome segregation and asymmetric inheritance of centrosomeassociated structures. In the second part, we will also review recent insight into the generation and function of sibling cell size asymmetry.

Centrosomes are inherently asymmetric and segregate non-randomly Centrosomes are the microtubule organizing centers (MTOCs) of animal cells, consisting of a pair of centrioles surrounded by pericentriolar material (PCM) [8]. Centrioles replicate semi conservatively; the old ‘mother’ centriole serves as a template for the generation of a young ‘daughter’ centriole, both of which go on to reform the PCM cloud and generate a new centrosome after separating. Several stem cell types have been reported to contain physically and molecularly asymmetric centrosomes, segregating non-randomly, leading to the hypothesis that centrosomes provide instructive cues to influence cell fate decisions [9–12,13]. For instance, Drosophila male germline stem cells and vertebrate neural stem cells inherit the older mother centrosome, whereas the younger daughter centriole is obtained by the differentiating sibling cell [9,12] (Figure 1a,b). However, Drosophila neural stem cells, called neuroblasts [2], or female germline stem cells (GSCs) inherit the younger daughter centrosome after cell division [10,11,13], indicating that stemness is not always associated with centriole age (Figure 1c,d).

http://dx.doi.org/10.1016/j.ceb.2014.09.005 0955-0674/# 2014 Elsevier Ltd. All right reserved.

Introduction Asymmetric cell division (ACD) generates cellular diversity by differentially segregating RNA and protein determinants into the two sibling cells [1]. ACD is utilized by both prokaryotes and eukaryotes to generate sibling cells with a different molecular identity, cell fate and behavior. Stem cells rely on ACD to generate differentiating siblings while regenerating the stem cell through selfrenewal [2–5]. Many of the key players and mechanisms controlling ACD are conserved between invertebrates and vertebrates [1,2]. A unifying principle that has emerged in the last years is that cell polarity controls Current Opinion in Cell Biology 2014, 31:84–91

The mechanism for biased centrosome segregation seems to be rooted in MTOC activity. For instance, Drosophila neuroblast centrosomes undergo an elaborate centrosome dematuration and rematuration cycle, in which the mother centriole sheds PCM right after centrosome separation and, as a consequence, loses its position on the apical cortex. It remains PCM-free during interphase, only regaining PCM and MTOC activity from prophase onwards. The daughter centriole, however, remains stationed in the apical half of the neuroblast because it retains PCM and MTOC activity throughout interphase [10,14,15]. Recently it was found that asymmetrically localized factors such as Centrobin (Cnb), the mitotic kinase Polo and Pericentrin (PCNT)-like protein (Plp) control PCM retention and thus asymmetric MTOC activity, ultimately affecting centrosome positioning and spindle orientation [11,16,17]. For instance, Cnb specifically localizes to the neuroblast daughter www.sciencedirect.com

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Figure 1

(a) Drosophila male germline

(b) Vertebrate neural stem cell GSC

Dd

Gb GSC

NSC NSC (d) Drosophila female germline

(c) Drosophila neuroblast

GSC

Nb

? Cb

GMC Nb Mother centrosome

GSC Daughter centrosome

Midbody Current Opinion in Cell Biology

Asymmetric centrosome and midbody inheritance. Segregation pattern of mother centrosome (red), daughter centrosome (green) and midbody (orange) in (a) Drosophila male germline stem cells (GSCs), (b) Vertebrate neural stem cells (NSCs), (c) Drosophila neuroblasts (Nbs) and (d) Drosophila female germline stem cells (GSCs). In NSCs, the midbody is released into the extracellular space and in Nbs, its fate is currently unknown. GMC; ganglion mother cells, Gb; gonialblast, Dd; differentiating daughter, CB; cystoblast.

centriole and is necessary and sufficient to retain PCM on the apical daughter centriole [11,16]. Polo is localized on the apical daughter centrosome throughout interphase and phosphorylates Cnb, which is required for PCM retention [14,16,18]. The mother centriole-containing centrosome does not localize Cnb and downregulates Polo after centrosomes separate and remains free of Polo during interphase. Only from prophase onwards, Polo returns to the basal centrosome, initiating its maturation [11,14,19]. How Polo localization is controlled is not clear but it was recently suggested that Plp, which localizes to both centrosomes albeit enriched on the mother, prevents premature Polo localization [17]. Furthermore, the centriolar protein Bld10 (Cep135 in vertebrates) is required to generate interphase centrosome asymmetry through shedding of Polo and subsequently PCM [19]. The molecular mechanism and function of centrosome asymmetry is incompletely understood, but it is clear that correct centrosome positioning is an important step in setting up spindle orientation [9,15,18]. During asymmetric cell division, the correct orientation of the mitotic spindle is very important to accurately segregate cell fate determinants, influencing stem cell homeostasis and differentiation [20]. Also, asymmetric centrosome segregation seems to be an evolutionary conserved mechanism since yeast spindle pole bodies are also distributed in a non-random fashion [21,22].

Non-random sister chromatid segregation Centrosomes are not the only subcellular components to segregate non-randomly. In yeast, mouse embryonic stem www.sciencedirect.com

(ES) cells and Drosophila female GSCs, sister chromatids segregate in a biased fashion [23–27]. Surprisingly, a recent report showed that in male GSCs, only the X and Y chromosomes segregate non-randomly, whereas autosomes are inherited randomly [28]. Biased X and Y chromosome segregation could be connected to the immortal strand hypothesis, which proposes that stem cells reduce the accumulation of replication-induced mutations by retaining the older template DNA strands [29]. However, GCSs do not retain the non-mortal strand [28]. The molecular mechanism underlying biased DNA segregation is still unclear but centrosome asymmetry could be connected with biased sister chromatid segregation. For instance, Centrosomin (Cnn), a major organizer of the pericentriolar matrix (PCM) [30], the SUN domain protein Klaroid (KOI) and the KASH domain protein Klarsicht (Klar) are all required for biased chromosome segregation [28,31]. SUN-domain and KASH-domain proteins are members of the LINC complex (linker of nucleoskeleton and cytoskeleton), tethering the nucleus via the nuclear envelope to cytoskeletal components such as microtubules and thus centrosomes. Since DNA is physically connected to centrosomes via kinetochores, it has been speculated that epigenetic marks and asymmetric kinetochore protein assembly could form a biased centrosome-DNA connection via microtubules, leading to non-random chromatid segregation [32]. Indeed, it was found that Dnmt2, a potential methyltransferase, contributes to biased X and Y sister chromatid segregation Current Opinion in Cell Biology 2014, 31:84–91

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through non-genetic mechanisms. Strikingly, in GSCs from heterozygous flies (dnmt2 /dnmt2+), inheriting the X chromosome from a mutant mother (dnmt2 /dnmt2 ) and the Y chromosome from a heterozygous father (dnmt2 /dnmt2+), only X chromosome segregation was randomized. This could suggest that the information enabling nonrandom sister chromatid segregation is primed during gametogenesis, transmitted to the zygote on single X and Y chromosomes, and maintained through many cell divisions during embryogenesis and adult tissue homeostasis [28] (Figure 2a). Intriguingly, a recent report also showed that in Drosophila male GSCs, certain histones segregate asymmetrically, Figure 2

(a) Drosophila male germline GSC

Gb X

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(b) Drosophila male germline Anaphase

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Old Histone H3 New Histone H3

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albeit the connection between non-random sister chromatid segregation and histone partitioning is unclear [33] (Figure 2b). Despite these intriguing observations, nonrandom DNA segregation does not seem to be a determinant of stem cell identity because mutants that randomize sister chromatid segregation do not affect germline stem cell identity [28]. Nevertheless, non-random sister chromatid segregation could influence cell robustness or aging [32].

Asymmetric segregation of the midbody Recently, a link between asymmetric centrosome inheritance and midbody segregation has also been observed. The midbody (MB), also called Flemming body, forms at the end of cytokinesis from overlapping plus ends of central spindle microtubules, recruiting various crosslinking proteins to form this electron dense structure. The MB is the final connection between dividing cells until abscission separates both sibling cells. Since abscission usually occurs asymmetrically, the MB is inherited by only one daughter cell [34–36]. Stem cells, induced pluripotent stem cells and also potential cancer stem cells have been reported to inherit the MB remnant together with the older mother centrosome [37]. However, a related study came to the opposite conclusion, since midbodies were found to be released in various cell lines and not retained by either sibling cell [38]. A similar situation has also been observed in vivo; neuroepithelial cells release apical MBs, carrying the stem cell and microdomain marker Prominin-1 into the extracellular space [39] (Figure 1b). Interestingly, it was found that in the Drosophila germline, MBs segregate asymmetrically with the younger daughter centrosome; male germline stem cells inherit the mother centrosome but not the MB, whereas female germline stem cells obtain the daughter centrosome and the MB (Figure 1a,d). Although MB segregation depends on functional centrosomes, it is unlikely that MBs carry inherent cell fate determinants since mutants that randomize MB inheritance do not drastically modulate stem cell identity [13].

Gb

Old Histone H3.3 New Histone H3.3 Current Opinion in Cell Biology

Non-random chromatid and histone segregation. (a) In Drosophila male GSCs, sister chromatids of the X chromosome (and Y chromosome; not represented for simplicity) segregate non-randomly together with the mother centrosome; the red X sister chromatid preferentially segregates with the GSC whereas the green X chromatid is inherited by the gonialblast. Autosomes segregate randomly and are shown in lighter colors. A putative connection between sister chromatids and the mother centrosome is established through the SUN-KASH complex and unknown proteins. (b) In Drosophila male GSCs, old (green squares) and new (orange squares) histones H3 segregate non-randomly; old H3s are preferentially inherited by GSC. By contrast, old (blue squares) and new (pink squares) histones H3.3 randomly segregate between GSCs and gonialblasts (Gbs). Current Opinion in Cell Biology 2014, 31:84–91

Asymmetric inheritance of centrosome associated primary cilium membrane Another centrosome-associated structure to segregate in a biased manner is the primary cilium, which is formed by the mother centriole in non-dividing cells. The primary cilium is an antenna-like structure, composed of nine microtubule doublets and surrounded by ciliary membrane (CM). This organelle serves as a signaling center and is an important regulator of proliferation and embryonic patterning [40]. It is generally accepted that the primary cilium disassembles before mitosis but is reformed in early G1 [8]. A recent report now describes the fate of the CM in dividing neocortical cells, human embryonic kidney (HEK293T) and mouse neuroblastoma (Neuro2a) cells, revealing that the CM is asymmetrically inherited by the self-renewed stem cell, whereas www.sciencedirect.com

Asymmetric cell division during development Roubinet and Cabernard 87

the daughter cell reestablishes a primary cilium [41]. The primary cilium extends from the apical membrane of epithelial neural stem cells (called apical progenitors (APs)), into the lateral ventricle, detecting signals from the cerebrospinal fluid [42]. Live imaging experiments with organotypic slices revealed that the CM internalizes at the G2-M phase transition, persisted intracellularly through mitosis and was subsequently asymmetrically inherited by one daughter, retaining stem cell character. Because the primary cilium is a signaling center, the CMinheriting cell could initiate earlier signaling activity, potentially affecting cell fate (Figure 3) [41]. Apical progenitors can switch from symmetric, amplifying divisions to asymmetric, neurogenic divisions [43] and asymmetric CM inheritance has been primarily observed during preneurogenic and early neurogenic stages. It will be interesting to learn how asymmetric primary cilia segregation is connected to symmetric and asymmetric progenitor divisions and fate.

Spindle-dependent and spindle-independent mechanisms for cleavage furrow positioning

Sibling cell size asymmetry

However, spindle-independent cleavage furrow positioning mechanisms have been recently discovered in several cell types and organisms [58–61]. For instance, asymmetrically dividing Drosophila neuroblasts utilize the polarity proteins Discs large 1 (Dlg1) and Partner of Inscuteable (Pins; AGS3/LGN in vertebrates) to asymmetrically localize Myosin, positioning the cleavage furrow off-center [58,62].

Sibling cell size difference is a form of physical asymmetry and occurs in several cell types and species such as dividing Saccharomyces cerevisiae cells, Drosophila neuroblasts and sensory organ precursor cells (SOPs) [44]. Similarly, physical asymmetry is also established during C. elegans development [4] as well as micromere producing cell divisions in sea urchins and mollusks [45–47]. Polar body forming divisions during meiosis are also highly asymmetric [48,49], generating a large oocyte that supports embryonic development. However, in most other cases, the physiological relevance for this cell-size asymmetry is unclear but could be involved in the regulation of the cell cycle and proliferation rates or affect cell fate [20,50,51]. How sibling cell size is generated is not entirely clear but might be cell type specific and involves several different mechanisms (Figure 4).

One mechanism to establish daughter cell size differences is through cleavage furrow positioning. In most metazoan cells the signals to accurately position the cleavage furrow originate from the spindle midzone, astral microtubules (MTs) or both and involves the Centralspindlin complex, triggering local RhoA activation and the subsequent placement and assembly of the contractile ring (reviewed in [52–55]). Many asymmetrically dividing cells — the first embryonic cell division in C. elegans is one of the best examples — displace the mitotic spindle through Dynein-mediated pulling forces, shifting furrow inducing cues towards one side of the cell (reviewed in [56]). Similarly, spindle-derived furrow inducing cues could be positioned off-cell center by changing spindle geometry. Drosophila neuroblasts develop an asymmetric spindle during anaphase, and it has been assumed that spindle geometry induces cell size asymmetry in this cell type [51,57] (Figure 4a,b).

Asymmetric Myosin localization, as a mechanism to generate sibling cell size differences, has also been observed in the C. elegans Q neuroblast lineage. Q neuroblasts give rise to a QR.a and a QR.p cell, both of which divide asymmetrically, generating three distinct neurons and two apoptotic cells [63]. QR.p cells utilize the spindle displacement mechanism to form unequal sized daughters, but the QR.a cells also localizes Myosin asymmetrically in a

Figure 3

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S/G2

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Mother centriole Daughter centriole Grand-daughter centriole BP

Ciliary axoneme w/ ciliary membrane

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Current Opinion in Cell Biology

Asymmetric inheritance of centrosome associated primary cilium membrane. The ciliary axoneme (brown) is formed by the mother centriole (red square). In S phase, both mother and daughter (green square) centrioles duplicate, generating two grand-daughter centrioles (white squares). Cilia partially disassemble, are endocytosed in G2 phase and remain internalized during mitosis. The cilia and its associated cilia membrane (blue) is preferentially inherited by the self-renewed apical progenitor (AP), whereas the basal progenitor (BP) reestablishes a primary cilium. www.sciencedirect.com

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88 Cell cycle, differentiation and disease

Figure 4

(a)

(b)

Central spindle

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furrow positioning cue

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Legend Cortical proteins Anillin, Myosin, Moesin Cortical contraction Cytoplasmic flow

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Symmetry breaking DNA cues Ran, Pp1-87B, Sds22 Cortical expansion Current Opinion in Cell Biology

Cellular and molecular mechanisms generating sibling cell size asymmetry. (a) An asymmetric cortical distribution of Dynein (blue circles) is decentering the mitotic spindle (black) through pulling forces (blue arrows), inducing cleavage furrow positioning off-cell center via the centralspindlin complex (blue oval). (b) The formation of longer astral microtubules (MTs; brown) on one side of the cell and/or an inherently asymmetric central spindle can also shift the cleavage furrow towards one side of the cell pole. (c) A symmetry breaking event on one pole of the cell can induce asymmetric Myosin (green) relocalization. Asymmetric Myosin distribution, putatively triggers an oriented cytoplasmic flow (thin blue arrows), causing apical cortical expansion. (d) During anaphase, kinetochore microtubules pull sister chromatids towards the cell poles. This DNA-cortex proximity allows proteins localized around DNA, such as Ran GTPase or the phosphatases Sds22/Pp1-87B, to deliver polar cortex modifying signals to the cell poles. This causes cortical proteins such as Myosin, Moesin or Anillin to be removed/inhibited, inducing membrane expansion at both poles (blue arrows). The equatorial contraction of the cleavage furrow might again induce a cytoplasmic flow, generating the force to expand the polar membrane. Cells displaying a decentered spindle and thus decentered DNA, could induce asymmetric polar extension based on asymmetric distribution of cortex modifying signals.

spindle-independent manner [61]. In wild type QR.a cells, Myosin is enriched at the anterior pole of dividing cells but mutations in the transcription factors HAM-1 or LIN-32 cause Myosin to be symmetrically distributed, resulting in a physical symmetric cell division. In ham-1 and lin-32 mutants, both QR.a daughter cells survive and adopt neuronal fate whereas in wild type, one sibling undergoes apoptosis and the other becomes a neuron. Interestingly, HAM-1 was found to be specifically involved in QR.a but not QR.p asymmetric division [64,65]. Most likely, HAM-1 and LIN-32 control asymmetric Myosin localization through specific effector genes. For instance, the HAM-1 target PIG-1 is a member of the PAR family proteins, well-known regulators of cell polarity and asymmetric cell division. PIG-1 could thus provide a connection between cell polarity and asymmetric Myosin localization, Current Opinion in Cell Biology 2014, 31:84–91

similarly to Pins and Dlg1 in Drosophila neuroblasts [58] (Figure 4c). Novel data also suggests that GRP-1, the sole C. elegans cytohesin, and the DEP domain-containing protein TOE-2 control sibling cell size asymmetry in the Q neuroblast lineage [66,67]. Cytohesins are Arf guanine nucleotide exchange factors (GEFs) that regulate membrane trafficking and actin cytoskeletal dynamics. Loss of GRP-1 results in daughter cells that are more similar in size, transforming the apoptotic daughter into its sister and thus producing extra neurons [66]. TOE-2 localizes to the plasma membrane and accumulates at the cleavage furrow. In QR.a cells, loss of toe-2 results in a more symmetric division and survival of the smaller QR.a daughter, which in wild type is fated to undergo apoptosis [67]. However, the relationship between GRP-1 and TOE-2 is currently unknown. www.sciencedirect.com

Asymmetric cell division during development Roubinet and Cabernard 89

Cortical expansion generates cell size asymmetry Asymmetric Myosin distribution has been proposed to drive unequal cortical expansion, pushing the cleavage furrow off-center [61,62]. For instance, Myosin enrichment on one side of the cell could create higher active cortical tension while at the same time reducing cortical stiffness on the opposite cell pole. A reduction in cortical stiffness is required to allow cortical expansion, but other cortical proteins such as Anillin or ERM proteins (Ezrin, Radixin and Moesin in vertebrates) also need to be inhibited or relocalized [68–71]. In symmetrically dividing cells, the phosphatases Sds22 and Pp1-87B inactivate dMoesin at polar regions to allow symmetric polar membrane expansion. Sds22 and Pp1-87B are associated with DNA during anaphase, suggesting that the proximity of chromosomes with the membrane could locally modulate the composition of the cortex [70,72]. Interestingly, a more direct role for a chromosome-derived signal in polar relaxation and subsequent expansion has recently been demonstrated in HeLA, Rpe1, BHK and tsBN2 cells [50]. These cells divide symmetrically but when the spindle, and thus also chromosomes, are experimentally shifted to one side of the cell at anaphase onset, Anillin and Myosin are locally inhibited, promoting asymmetric membrane expansion. A prime candidate for the chromosome-derived signal is RanGTP, forming a gradient on chromosomes during mitosis [73]. Indeed, if the formation of RanGTP is prevented under conditions when the chromosomes were displaced, the cortex cannot be modified in the vicinity of the DNA and membrane extension does not occur. Thus, a chromosome derived RanGTP gradient inhibits cortical proteins specifically at polar regions. This causes a local weakening of the cortex and promotes its expansion during anaphase [50]. It has to be noted that this mechanism corrects for mispositioned spindles in symmetrically dividing cells, ensuring that both siblings end up with the same size. Whether asymmetrically dividing cells in vivo utilize the same mechanism to control asymmetric membrane expansion remains to be seen. For instance, asymmetry in DNA proximity between the two poles of asymmetrically dividing cells could inactivate cortical proteins (dMoesin, Myosin, Anillin) preferentially at one pole, inducing cortical contraction in anaphase anisotropic (Figure 4d,e). In agreement with this model is a previous study, showing that unbalanced cortical contractions in HeLa cells are able to shift the cleavage furrow towards polar regions [60].

Conclusion Asymmetric segregation of centrosomes, centrosomeassociated structures but also other organelles is probably more common than previously anticipated. Similarly, cell shape changes during mitosis can trigger transient asymmetries, which, if stabilized could result in physical asymmetric cell division. The biological significance of www.sciencedirect.com

these forms of asymmetry is not always clear, but could affect cell behavior, only detectable on a longer time scale. In the future, it will be interesting to learn more about the specific mechanisms involved and the consequence on cell fate and behavior.

Acknowledgements We thank members of the Cabernard lab for helpful discussions and critical reading of the manuscript. This work was supported by the Swiss National Science Foundation (SNSF). C.R. is supported by an EMBO long-term postdoctoral fellowship.

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Current Opinion in Cell Biology 2014, 31:84–91