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Determination of the Cleavage Plane in Early C. Elegans Embryos ANRV361-GE42-18 ARI 11 October 2008 11:24 ANNUAL Determination of the REVIEWS Further Click here for quick links to Annual Reviews content online, Cleavage Plane in Early including: • Other articles in this volume Embryos • Top cited articles C. elegans • Top downloaded articles • Our comprehensive search Matilde Galli and Sander van den Heuvel Developmental Biology, Utrecht University, 3584 CH Utrecht, The Netherlands; email: [email protected] Annu. Rev. Genet. 2008. 42:389–411 Key Words First published online as a Review in Advance on cytokinesis, cleavage plane, asymmetric division, spindle positioning, August 18, 2008 C. elegans The Annual Review of Genetics is online at genet.annualreviews.org Abstract This article’s doi: Cells split in two at the final step of each division cycle. This division 10.1146/annurev.genet.40.110405.090523 Access provided by Utrecht University on 12/02/17. For personal use only. normally bisects through the middle of the cell and generates two equal Annu. Rev. Genet. 2008.42:389-411. Downloaded from www.annualreviews.org Copyright c 2008 by Annual Reviews. daughters. However, developmental signals can change the plane of cell All rights reserved cleavage to facilitate asymmetric segregation of fate determinants and 0066-4197/08/1201-0389$20.00 control the position and relative sizes of daughter cells. The anaphase spindle instructs the site of cell cleavage in animal cells, hence its po- sition is critical in the regulation of symmetric vs asymmetric cell divi- sion. Studies in a variety of models identified evolutionarily conserved mechanisms that control spindle positioning. However, how the spin- dle determines the cleavage site is poorly understood. Recent results in Caenorhabditis elegans indicate dual functions for a Gα pathway in posi- tioning the spindle and cleavage furrow. We review asymmetric division of the C. elegans zygote, with a focus on microtubule-cortex interactions that position the spindle and cleavage plane. 389 ANRV361-GE42-18 ARI 11 October 2008 11:24 INTRODUCTION TO THE TOPIC ically to one of the daughter cells, which of- AND MODEL ten also differs in size from the other daughter. Such “intrinsically asymmetric divisions” pro- Asymmetric Cell division is one of the most fascinating and mote cell diversity and are one of the mecha- divisions: divisions fundamental processes in the life of an organ- nisms by which stem and progenitor cells com- that give rise to ism. The actual division process takes place in different daughters. bine self-renewal with production of differen- two coordinated steps during the final phase of Here, we only tiating daughters (10, 33). The position of the the cell cycle, named M phase (Figure 1a). Dur- consider intrinsically cleavage plane forms a critical aspect of such asymmetric divisions, ing nuclear division or mitosis, the duplicated asymmetric divisions (Figure 1b,c). in which different fates genetic material is separated into two identi- The protein apparatus that segregates the are determined by the cal sets. Next, the cytoplasm is cleaved dur- division process chromosomes, the mitotic spindle, also deter- ing cytokinesis, thereby forming two separate mines the plane of cell cleavage. Because the daughter cells. With only rare exceptions, cells cleavage plane bisects the spindle, chromo- cleave in coordination with nuclear division somes end up in different daughter cells. In and in between the segregated chromosomes. some cells, such as plant and fungal cells, the This coupling between mitosis and cytokinesis division plane is established prior to mitosis supports the maintenance of an intact genome and the mitotic spindle is oriented with re- through many rounds of cell division and helps spect to this predetermined site (reviewed in the equal distribution of cellular components Reference 7). In contrast, in animal cells the to the progeny cells. However, not all cell di- position of the spindle determines where the visions are meant to form identical daughters: cell will cleave. Hence, the position or symme- Certain asymmetric divisions segregate cellular try of the mitotic spindle is regulated in order components such as fate determinants specif- a Prophase Prometaphase Metaphase Anaphase A Anaphase B/ Telophase Cytokinesis b Default cleavage plane Spindle rotation Spindle displacement Access provided by Utrecht University on 12/02/17. For personal use only. Annu. Rev. Genet. 2008.42:389-411. Downloaded from www.annualreviews.org c Symmetric division Asymmetric division Figure 1 (a) Schematic representation of the sequential stages of mitosis. Chromosomal DNA (red ), microtubules ( gray lines), centrosomes ( gray circles), and the nuclear envelopes (blue). (b) Illustration of how changes in the position of the spindle alter the plane of cell cleavage and thereby the size and placement of daughter cells. (c) Polarized cells can switch from symmetric to asymmetric divisions by altering their cleavage plane. The apical domain ( green), basal domain (tan), and cell junctions (blue) are shown. 390 Galli · van den Heuvel ANRV361-GE42-18 ARI 11 October 2008 11:24 to control the cell cleavage plane (Figure 1b). acto-myosin network at the cortex and micro- Rotation of the spindle changes the position of tubules of the spindle in determining the cell daughter cells and distribution of determinants, cleavage plane. whereas displacing the spindle off-center leads to daughter cells of unequal sizes. As the posi- tion of the spindle dictates the plane of cleavage, Cell Cleavage in C. elegans it is of fundamental importance to understand In a relatively short time, C. elegans has ar- what molecular mechanisms control the spin- guably become the leading model in stud- dle position, and how the spindle controls the ies of cleavage plane determination. Reasons place of cell cleavage. for this status include the reproducible cell Since the classical experiments by Rappa- lineage, which incorporates asymmetric cell port with sand dollar eggs (85), much has been division and cytokinesis from the very first di- learned about the interconnection between vision onward. Thus, cleavage can be stud- spindle positioning and cell cleavage determi- ied when the cells are still large (length/width nation. Genetic studies in the fruit fly Drosophila of the zygote ∼50/30 μm) and spindles and melanogaster and nematode Caenorhabditis ele- chromosomes easily observable. Equally im- gans revealed several molecular pathways that portant is the genetic tractability. Embryonic control the cleavage plane during animal de- functions of genes with general roles in cy- velopment (reviewed in References 10, 33). As tokinesis have been discovered though rela- an example, during stem cell divisions in the tively rare mutations (including temperature- Drosophila male germline, the mother centro- sensitive and maternal-effect lethal mutants) some maintains a fixed position so that the (56, 72, 78) as well as large-scale and genome- spindle forms away from the stem cell niche wide RNA interference (RNAi) screens (35, (116, 117). Consequently, the subsequent divi- 81, 99; http://nematoda.bio.nyu.edu). Sev- sion produces another stem cell in contact with eral more specialized techniques can be added the niche and one daughter that initiates a dif- to such experiments, including the introduction ferentiation program. Stem cell-like divisions of of drugs (e.g., 46, 104), culturing of blastomeres the larval neuroblasts in Drosophila use a fixed that have been removed from eggs (e.g., 30, 50), centrosome as well, and this centrosome acts and severing of the spindle with a UV laser, also as the major microtubule-nucleation cen- as introduced by Hyman (40, 49). Green fluo- ter (86). Hence, this spindle is asymmetric itself, rescent protein (GFP)-tagged proteins can be and places the cleavage plane off center to pro- expressed in the germline and early embryos mote production of another large neuroblast as through the introduction of low-copy trans- well as a smaller neural precursor. genes (83), and followed by time-lapse fluores- Access provided by Utrecht University on 12/02/17. For personal use only. In C. elegans, the positions of the spindle cence microscopy. The combination of these Annu. Rev. Genet. 2008.42:389-411. Downloaded from www.annualreviews.org and cell cleavage plane are tightly regulated and approaches allows for detailed analysis of the guide a reproducible pattern of asymmetric and molecular basis of cleavage-plane regulation in symmetric divisions throughout development. C. elegans. Decades of extensive studies have revealed evo- The framework for all cell division studies lutionarily conserved mechanisms that control is the C. elegans cell lineage (105). This lin- the position of the spindle and cleavage plane. eage starts with fertilization, followed by two Several recent results start to shed light on the consecutive highly asymmetric meiotic divi- possible connection between the spindle appa- sions. These divisions produce two small polar ratus and placement of the acto-myosin con- bodies, as the compact meiotic spindle segre- tractile ring in cytokinesis. In this review, we gates the chromosomes in close proximity of summarize the current understanding of asym- the cortex (Figures 2, 3 top). Subsequently, metric division of the one-cell C. elegans em- the maternal and paternal pronuclei meet in bryo, focusing on the connections between the the posterior and migrate toward the center www.annualreviews.org • Cleavage Plane in C. elegans 391 ANRV361-GE42-18 ARI 11 October 2008 11:24 a b PAR-3 Centrosome PAR-2 Nucleus PAR-2/PAR-3 Polar body Figure 2 The establishment of polarity in the early C. elegans embryo. For details, see text. (centration), while they rotate and the mitotic In summary, the position of the cleavage plane spindle assembles along the anterior-posterior is highly regulated in C. elegans and critical in axis of the zygote (P0). Following degradation establishing the body axes in the early embryo of the nuclear envelopes, the spindle aligns the as well as in generating the proper cell lineages chromosomes at the metaphase plate in the throughout development.
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