Asymmetric cell division in C. elegans: cortical polarity and spindle positioning.

The one-cell Caenorhabditis elegans embryo divides asymmetrically into a larger and smaller blastomere, each with a different fate. How does such asymmetry arise? The sperm-supplied centrosome establishes an axis of polarity in the embryo that is transduced into the establishment of anterior and posterior cortical domains. These cortical domains define the polarity of the embryo, acting upstream of the PAR proteins. The PAR proteins, in turn, determine the subsequent segregation of fate determinants and the plane of cell division. We address how cortical asymmetry could be established, relying on data from C. elegans and other polarized cells, as well as from applicable models. We discuss how cortical polarity influences spindle position to accomplish an asymmetric division, presenting the current models of spindle orientation and anaphase spindle displacement. We focus on asymmetric cell division as a function of the actin and microtubule cytoskeletons, emphasizing the cell biology of polarity.

[1]  A. Suzuki,et al.  Mammalian Lgl Forms a Protein Complex with PAR-6 and aPKC Independently of PAR-3 to Regulate Epithelial Cell Polarity , 2003, Current Biology.

[2]  K. Oegema,et al.  Functional Analysis of Kinetochore Assembly in Caenorhabditis elegans , 2001, The Journal of cell biology.

[3]  Gary G. Borisy,et al.  Self-polarization and directional motility of cytoplasm , 1999, Current Biology.

[4]  J. Denegre,et al.  Cleavage planes in frog eggs are altered by strong magnetic fields. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Fumio Matsumura,et al.  Phosphorylation of Myosin-Binding Subunit (Mbs) of Myosin Phosphatase by Rho-Kinase in Vivo , 1999, The Journal of cell biology.

[6]  Steven N. Hird,et al.  Cortical and cytoplasmic flow polarity in early embryonic cells of Caenorhabditis elegans , 1993, The Journal of cell biology.

[7]  B. Bowerman,et al.  The anaphase-promoting complex and separin are required for embryonic anterior-posterior axis formation. , 2002, Developmental cell.

[8]  P. Gönczy,et al.  Cyk-4 , 2000, The Journal of cell biology.

[9]  T. Pawson,et al.  A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl , 2003, Nature Cell Biology.

[10]  J. Ahringer,et al.  TAC-1, a Regulator of Microtubule Length in the C. elegans Embryo , 2003, Current Biology.

[11]  J. White,et al.  On the mechanisms of cytokinesis in animal cells. , 1983, Journal of theoretical biology.

[12]  S. Strome,et al.  C. elegans PAR Proteins Function by Mobilizing and Stabilizing Asymmetrically Localized Protein Complexes , 2004, Current Biology.

[13]  Anthony A. Hyman,et al.  Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo , 2001, Nature.

[14]  D. St Johnston,et al.  Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis formation. , 2002, Developmental cell.

[15]  K. Kemphues,et al.  A non-muscle myosin required for embryonic polarity in Caenorhabditis elegans , 1996, Nature.

[16]  Yoshiharu Matsuura,et al.  Phosphorylation and Activation of Myosin by Rho-associated Kinase (Rho-kinase)* , 1996, The Journal of Biological Chemistry.

[17]  S. Perry,et al.  Purification and properties of myosin light-chain kinase from fast skeletal muscle. , 1977, The Biochemical journal.

[18]  Jonathon Howard,et al.  The Distribution of Active Force Generators Controls Mitotic Spindle Position , 2003, Science.

[19]  J. Ahringer,et al.  Axis determination in C. elegans: initiating and transducing polarity. , 2001, Current opinion in genetics & development.

[20]  D. Baillie,et al.  A Formin Homology Protein and a Profilin Are Required for Cytokinesis and Arp2/3-Independent Assembly of Cortical Microfilaments in C. elegans , 2002, Current Biology.

[21]  R. Adelstein,et al.  Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity , 1975, Nature.

[22]  D. Shakes,et al.  Anucleate Caenorhabditis elegans sperm can crawl, fertilize oocytes and direct anterior-posterior polarization of the 1-cell embryo. , 2000, Development.

[23]  K. Kemphues,et al.  Mutations in the par genes of Caenorhabditis elegans affect cytoplasmic reorganization during the first cell cycle. , 1990, Developmental biology.

[24]  B. Bowerman,et al.  Centrosome maturation and mitotic spindle assembly in C. elegans require SPD-5, a protein with multiple coiled-coil domains. , 2002, Developmental cell.

[25]  J. Sellers,et al.  Effect of multiple phosphorylations of smooth muscle and cytoplasmic myosins on movement in an in vitro motility assay. , 1989, The Journal of biological chemistry.

[26]  Sebastian A. Leidel,et al.  Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome III , 2000, Nature.

[27]  Nicholas H. Brown,et al.  Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system , 1999, Nature Cell Biology.

[28]  K. Kemphues,et al.  par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed , 1995, Cell.

[29]  Lesilee S. Rose,et al.  LET-99 determines spindle position and is asymmetrically enriched in response to PAR polarity cues in C. elegans embryos. , 2002, Development.

[30]  J. Gerhart,et al.  Determination of the dorsal-ventral axis in eggs of Xenopus laevis: complete rescue of uv-impaired eggs by oblique orientation before first cleavage. , 1980, Developmental biology.

[31]  José-Eduardo Gomes,et al.  Caenorhabditis elegans par genes , 2002, Current Biology.

[32]  G. Seydoux,et al.  Polarization of the anterior–posterior axis of C. elegans is a microtubule-directed process , 2000, Nature.

[33]  K. Kemphues,et al.  Control of cleavage spindle orientation in Caenorhabditis elegans: the role of the genes par-2 and par-3. , 1995, Genetics.

[34]  K. Kemphues,et al.  PAR-2 is asymmetrically distributed and promotes association of P granules and PAR-1 with the cortex in C. elegans embryos. , 1996, Development.

[35]  Kerry Bloom,et al.  Dynamic Microtubules Lead the Way for Spindle Positioning , 2004, Nature Reviews Molecular Cell Biology.

[36]  D. Albertson.  Formation of the first cleavage spindle in nematode embryos. , 1984, Developmental biology.

[37]  Jingsong Xu,et al.  Divergent Signals and Cytoskeletal Assemblies Regulate Self-Organizing Polarity in Neutrophils , 2003, Cell.

[38]  S. Perry,et al.  Phosphorylation of the light-chain components of myosin from cardiac and red skeletal muscles. , 1975, The Biochemical journal.

[39]  H. Benink,et al.  Analysis of cortical flow models in vivo. , 2000, Molecular biology of the cell.

[40]  S. Bisgrove,et al.  Asymmetric cell division in fucoid algae: a role for cortical adhesions in alignment of the mitotic apparatus. , 2001, Journal of cell science.

[41]  S. Strome,et al.  An analysis of the role of microfilaments in the establishment and maintenance of asymmetry in Caenorhabditis elegans zygotes. , 1988, Developmental biology.

[42]  P. Mains,et al.  Rho-binding kinase (LET-502) and myosin phosphatase (MEL-11) regulate cytokinesis in the early Caenorhabditis elegans embryo. , 2002, Journal of cell science.

[43]  W. H. Clark,et al.  Cell-cell association directed mitotic spindle orientation in the early development of the marine shrimp Sicyonia ingentis. , 1997, Development.

[44]  K. Kemphues,et al.  par-6, a gene involved in the establishment of asymmetry in early C. elegans embryos, mediates the asymmetric localization of PAR-3. , 1996, Development.

[45]  Bruce Bowerman,et al.  Heads or tails: cell polarity and axis formation in the early Caenorhabditis elegans embryo. , 2002, Developmental cell.

[46]  Anthony A. Hyman,et al.  Caenorhabditis elegans TAC-1 and ZYG-9 Form a Complex that Is Essential for Long Astral and Spindle Microtubules , 2003, Current Biology.

[47]  D. Pellman,et al.  Positioning of the mitotic spindle by a cortical-microtubule capture mechanism. , 2000, Science.

[48]  L. Stein,et al.  RNAi analysis of genes expressed in the ovary of Caenorhabditis elegans , 2000, Current Biology.

[49]  M. Welch,et al.  The world according to Arp: regulation of actin nucleation by the Arp2/3 complex. , 1999, Trends in cell biology.

[50]  M. Fuller,et al.  Orientation of Asymmetric Stem Cell Division by the APC Tumor Suppressor and Centrosome , 2003, Science.

[51]  F. Piano,et al.  Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. , 1998, Development.

[52]  P. Gönczy,et al.  zyg-8, a gene required for spindle positioning in C. elegans, encodes a doublecortin-related kinase that promotes microtubule assembly. , 2001, Developmental cell.

[53]  Hye Kyong Kweon,et al.  Phosphorylation-Dependent Binding of 14-3-3 to the Polarity Protein Par3 Regulates Cell Polarity in Mammalian Epithelia , 2003, Current Biology.

[54]  S. van den Heuvel,et al.  A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C elegans. , 2003, Genes & development.

[55]  B. Bowerman,et al.  The Nonmuscle Myosin Regulatory Light Chain Gene mlc-4 Is Required for Cytokinesis, Anterior-Posterior Polarity, and Body Morphology during Caenorhabditis elegans Embryogenesis , 1999, The Journal of cell biology.

[56]  J. Ahringer,et al.  Distinct roles for Galpha and Gbetagamma in regulating spindle position and orientation in Caenorhabditis elegans embryos. , 2001, Nature cell biology.

[57]  A. Schetter,et al.  Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases , 2003, Development.

[58]  E. Salmon,et al.  Stability of microtubule attachment to metaphase kinetochores in PtK1 cells. , 1990, Journal of cell science.

[59]  S. Inoué,et al.  Studies of unequal cleavage in molluscs. II: Asymmetric nature of the two asters , 1987 .

[60]  E. Salmon,et al.  Kinetochore microtubules shorten by loss of subunits at the kinetochores of prometaphase chromosomes. , 1991, Journal of cell science.

[61]  R. Benton,et al.  Drosophila PAR-1 and 14-3-3 Inhibit Bazooka/PAR-3 to Establish Complementary Cortical Domains in Polarized Cells , 2003, Cell.

[62]  H. Schnabel,et al.  cyk-1: a C. elegans FH gene required for a late step in embryonic cytokinesis. , 1998, Journal of cell science.

[63]  A. Hyman,et al.  Determination of cell division axes in the early embryogenesis of Caenorhabditis elegans , 1987, The Journal of cell biology.

[64]  J. Labbé,et al.  PAR Proteins Regulate Microtubule Dynamics at the Cell Cortex in C. elegans , 2003, Current Biology.

[65]  Lesilee S. Rose,et al.  LET-99 opposes Gα/GPR signaling to generate asymmetry for spindle positioning in response to PAR and MES-1/SRC-1 signaling , 2003, Development.

[66]  Takashi Shimizu,et al.  Unequal cleavage in the early Tubifex embryo , 1998, Development, growth & differentiation.

[67]  Lesilee S. Rose,et al.  PAR-dependent and geometry-dependent mechanisms of spindle positioning , 2003, The Journal of cell biology.

[68]  Contrasting patterns of mitochondrial redistribution in the early lineages of Caenorhabditis elegans and Acrobeloides sp. PS1146. , 2003, Developmental biology.

[69]  I. Macara.  Parsing the Polarity Code , 2004, Nature Reviews Molecular Cell Biology.

[70]  J. Gerhart,et al.  Localization and induction in early development of Xenopus. , 1984, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[71]  Steven N. Hird,et al.  Specification of the anteroposterior axis in Caenorhabditis elegans. , 1996, Development.

[72]  J. Cooper,et al.  Transient localized accumulation of actin in Caenorhabditis elegans blastomeres with oriented asymmetric divisions. , 1994, Development.

[73]  Pierre Gönczy,et al.  TAC-1 and ZYG-9 Form a Complex that Promotes Microtubule Assembly in C. elegans Embryos , 2003, Current Biology.

[74]  B. Bowerman,et al.  Myosin and the PAR proteins polarize microfilament-dependent forces that shape and position mitotic spindles in Caenorhabditis elegans , 2003, The Journal of cell biology.

[75]  M. Glotzer,et al.  Centrosome separation and central spindle assembly act in redundant pathways that regulate microtubule density and trigger cleavage furrow formation. , 2003, Developmental cell.

[76]  J. Ahringer,et al.  Distinct roles for Gα and Gβγ in regulating spindle position and orientation in Caenorhabditis elegans embryos , 2001, Nature Cell Biology.

[77]  D. Taylor,et al.  Modulation of contraction by gelation/solation in a reconstituted motile model , 1991, The Journal of cell biology.

[78]  J. Kendrick‐Jones,et al.  Light-chain phosphorylation controls the conformation of vertebrate non-muscle and smooth muscle myosin molecules , 1983, Nature.

[79]  John G. White,et al.  The dynactin complex is required for cleavage plane specification in early Caenorhabditis elegans embryos , 1998, Current Biology.

[80]  Kozo Kaibuchi,et al.  Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase) , 1996, Science.

[81]  G. Oster,et al.  Kinematics of gray crescent formation in Xenopus eggs: the displacement of subcortical cytoplasm relative to the egg surface. , 1986, Developmental biology.

[82]  J. White,et al.  The spd-2 gene is required for polarization of the anteroposterior axis and formation of the sperm asters in the Caenorhabditis elegans zygote. , 2000, Developmental biology.

[83]  D. Costello,et al.  ON THE ORIENTATION OF CENTRIOLES IN DIVIDING CELLS, AND ITS SIGNIFICANCE: A NEW CONTRIBUTION TO , 1961 .

[84]  H. Nishida,et al.  Centrosome‐attracting body: A novel structure closely related to unequal cleavages in the ascidian embryo , 1998, Development, growth & differentiation.

[85]  K. Kemphues,et al.  PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos. , 1999, Development.

[86]  A. Hyman,et al.  Morphogenetic Properties of Microtubules and Mitotic Spindle Assembly , 1996, Cell.

[87]  W. Wood,et al.  Generation of asymmetry and segregation of germ-line granules in early C. elegans embryos , 1983, Cell.

[88]  J. White,et al.  Cortical flow in animal cells. , 1988, Science.

[89]  Magdalena Zernicka-Goetz,et al.  Role for sperm in spatial patterning of the early mouse embryo , 2001, Nature.

[90]  S. Strome,et al.  Brief cytochalasin-induced disruption of microfilaments during a critical interval in 1-cell C. elegans embryos alters the partitioning of developmental instructions to the 2-cell embryo. , 1990, Development.

[91]  C. Doe.  Cell polarity: the PARty expands , 2001, Nature Cell Biology.

[92]  K. Kemphues,et al.  Pseudocleavage is dispensable for polarity and development in C. elegans embryos. , 1995, Developmental biology.

[93]  C. Rieder,et al.  Mitosis in primary cultures of Drosophila melanogaster larval neuroblasts. , 2002, Journal of cell science.

[94]  Pierre Gönczy,et al.  Translation of Polarity Cues into Asymmetric Spindle Positioning in Caenorhabditis elegans Embryos , 2003, Science.

[95]  D. Morton,et al.  Identification of genes required for cytoplasmic localization in early C. elegans embryos , 1988, Cell.

[96]  J G White,et al.  Laterally Mobile, Cortical Tension Elements Can Self‐Assemble into a Contractile Ring , 1990, Annals of the New York Academy of Sciences.

[97]  James A. Spudich,et al.  Capping of surface receptors and concomitant cortical tension are generated by conventional myosin , 1989, Nature.

[98]  R. Dumollard,et al.  Phases of cytoplasmic and cortical reorganizations of the ascidian zygote between fertilization and first division. , 1999, Development.

[99]  S. Inoué,et al.  Micromanipulation studies of the asymmetric positioning of the maturation spindle in Chaetopterus sp. oocytes: I. Anchorage of the spindle to the cortex and migration of a displaced spindle. , 1988, Cell motility and the cytoskeleton.

[100]  J. Ahringer,et al.  Asymmetrically Distributed C. elegans Homologs of AGS3/PINS Control Spindle Position in the Early Embryo , 2003, Current Biology.

[101]  M. Bjerknes.  Physical theory of the orientation of astral mitotic spindles. , 1986, Science.

[102]  E. Salmon,et al.  Dynamic positioning of mitotic spindles in yeast: role of microtubule motors and cortical determinants. , 2000, Molecular biology of the cell.

[103]  Y. Wang,et al.  Mammalian spindle orientation and position respond to changes in cell shape in a dynein-dependent fashion. , 2000, Molecular biology of the cell.

[104]  C. Doe,et al.  Asymmetric cell division: fly neuroblast meets worm zygote. , 2001, Current opinion in cell biology.

[105]  K. Oegema,et al.  Rappaport rules: cleavage furrow induction in animal cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[106]  G. Seydoux,et al.  Anterior-Posterior Polarity in C. elegans and Drosophila--PARallels and Differences , 2002, Science.

[107]  K. Kemphues,et al.  ZYG-9, A Caenorhabditis elegans Protein Required for Microtubule Organization and Function, Is a Component of Meiotic and Mitotic Spindle Poles , 1998, The Journal of cell biology.

[108]  Taylor,et al.  In vitro models of tail contraction and cytoplasmic streaming in amoeboid cells , 1993, The Journal of cell biology.

[109]  A. Hyman,et al.  Centrosome movement in the early divisions of Caenorhabditis elegans: a cortical site determining centrosome position , 1989, The Journal of cell biology.

[110]  B. Bowerman,et al.  Cell polarity and the cytoskeleton in the Caenorhabditis elegans zygote. , 2003, Annual review of genetics.

[111]  M. Morgan,et al.  Myosin light-chain phosphatase. , 1976, The Biochemical journal.

[112]  K. Mechtler,et al.  The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl , 2003, Nature.

[113]  F. Piano,et al.  Gene Clustering Based on RNAi Phenotypes of Ovary-Enriched Genes in C. elegans , 2002, Current Biology.

[114]  J. Gerhart,et al.  A reinvestigation of the role of the grey crescent in axis formation in Xenopus laevis , 1981, Nature.

[115]  J. White,et al.  Centrosome dynamics in early embryos of Caenorhabditis elegans. , 1998, Journal of cell science.

[116]  K. Kemphues,et al.  Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos , 1995, Cell.

[117]  K. Kaibuchi,et al.  Rho-associated Kinase Directly Induces Smooth Muscle Contraction through Myosin Light Chain Phosphorylation* , 1997, The Journal of Biological Chemistry.