An agent-based model contrasts opposite effects of dynamic and stable microtubules on cleavage furrow positioning

From experiments by Foe and von Dassow (Foe, V.E., and G. von Dassow. 2008. J. Cell Biol. 183:457–470) and others, we infer a molecular mechanism for positioning the cleavage furrow during cytokinesis. Computer simulations reveal how this mechanism depends on quantitative motor-behavior details and explore how robustly this mechanism succeeds across a range of cell sizes. The mechanism involves the MKLP1 (kinesin-6) component of centralspindlin binding to and walking along microtubules to stimulate cortical contractility where the centralspindlin complex concentrates. The majority of astral microtubules are dynamically unstable. They bind most MKLP1 and suppress cortical Rho/myosin II activation because the tips of unstable microtubules usually depolymerize before MKLP1s reach the cortex. A subset of astral microtubules stabilizes during anaphase, becoming effective rails along which MKLP1 can actually reach the cortex. Because stabilized microtubules aim statistically at the equatorial spindle midplane, that is where centralspindlin accumulates to stimulate furrow formation.

[1]  M. Glotzer,et al.  An ECT2–centralspindlin complex regulates the localization and function of RhoA , 2005, The Journal of cell biology.

[2]  Timothy J. Mitchison,et al.  Determining the position of the cell division plane , 2003, Nature.

[3]  T. Kitamura,et al.  MgcRacGAP Is Involved in Cytokinesis through Associating with Mitotic Spindle and Midbody* , 2001, The Journal of Biological Chemistry.

[4]  J. Matulienė,et al.  Kinesin-like protein CHO1 is required for the formation of midbody matrix and the completion of cytokinesis in mammalian cells. , 2002, Molecular biology of the cell.

[5]  B. Prescott,et al.  Means of increasing the tolerated dose of isoniazid-streptomycin mixtures in mice. II. Certain vitamins. , 1960, Antibiotics & chemotherapy.

[6]  P. Wadsworth,et al.  Dual role for microtubules in regulating cortical contractility during cytokinesis , 2008, Journal of Cell Science.

[7]  H. Bellen,et al.  pavarotti encodes a kinesin-like protein required to organize the central spindle and contractile ring for cytokinesis. , 1998, Genes & development.

[8]  R. Rappaport,et al.  Establishment of the mechanism of cytokinesis in animal cells. , 1986, International review of cytology.

[9]  J. Spudich,et al.  Rho Kinase's Role in Myosin Recruitment to the Equatorial Cortex of Mitotic Drosophila S2 Cells Is for Myosin Regulatory Light Chain Phosphorylation , 2006, PloS one.

[10]  G. von Dassow,et al.  Rho GTPase activity zones and transient contractile arrays , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  William Sullivan,et al.  Cortical recruitment of nonmuscle myosin II in early syncytial Drosophila embryos , 2002, The Journal of cell biology.

[12]  K. Nakao,et al.  p140mDia, a mammalian homolog of Drosophila diaphanous,is a target protein for Rho small GTPase and is a ligand for profilin , 1997, The EMBO journal.

[13]  S. Narumiya,et al.  Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow , 2000, Oncogene.

[14]  S. Yonemura,et al.  Centralspindlin regulates ECT2 and RhoA accumulation at the equatorial cortex during cytokinesis , 2006, Journal of Cell Science.

[15]  S. Wasserman,et al.  Functional analysis of the Drosophila diaphanous FH protein in early embryonic development. , 2000, Development.

[16]  E. Nigg,et al.  Cell cycle regulation of central spindle assembly , 2004, Nature.

[17]  E. Munro,et al.  Astral Signals Spatially Bias Cortical Myosin Recruitment to Break Symmetry and Promote Cytokinesis , 2007, Current Biology.

[18]  François Nédélec,et al.  Dynamics of microtubule aster formation by motor complexes , 2001 .

[19]  J Hardin,et al.  Cytokinesis and midzone microtubule organization in Caenorhabditis elegans require the kinesin-like protein ZEN-4. , 1998, Molecular biology of the cell.

[20]  V. Foe,et al.  Stable and dynamic microtubules coordinately shape the myosin activation zone during cytokinetic furrow formation , 2008, The Journal of cell biology.

[21]  M. Zavortink,et al.  Tum/RacGAP50C provides a critical link between anaphase microtubules and the assembly of the contractile ring in Drosophila melanogaster , 2005, Journal of Cell Science.

[22]  G. Fang,et al.  MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Miki,et al.  Human Ect2 Is an Exchange Factor for Rho Gtpases, Phosphorylated in G2/M Phases, and Involved in Cytokinesis , 1999, The Journal of cell biology.

[24]  H. Coon,et al.  Thyroid cells in culture. , 1979, International review of cytology. Supplement.

[25]  N. Galjart,et al.  Cytoplasmic linker proteins promote microtubule rescue in vivo , 2002, The Journal of cell biology.

[26]  A C Maggs,et al.  Dynamic concentration of motors in microtubule arrays. , 2000, Physical review letters.

[27]  A. Hyman,et al.  A cytokinesis furrow is positioned by two consecutive signals , 2005, Nature.

[28]  D. Glover,et al.  Mutations in orbit/mast reveal that the central spindle is comprised of two microtubule populations, those that initiate cleavage and those that propagate furrow ingression , 2004, The Journal of cell biology.

[29]  P. Wadsworth.  Cytokinesis: Rho Marks the Spot , 2005, Current Biology.

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

[31]  Jonathan Dinerstein,et al.  Modeling and rendering viscous liquids , 2004, Comput. Animat. Virtual Worlds.

[32]  M. Glotzer,et al.  Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. , 2002, Developmental cell.

[33]  E. Nigg,et al.  Influence of human Ect2 depletion and overexpression on cleavage furrow formation and abscission , 2006, Journal of Cell Science.

[34]  D. Glover,et al.  RacGAP50C is sufficient to signal cleavage furrow formation during cytokinesis , 2006, Journal of Cell Science.

[35]  H. Bellen,et al.  A putative exchange factor for Rho1 GTPase is required for initiation of cytokinesis in Drosophila. , 1999, Genes & development.

[36]  E. Salmon,et al.  The role of pre- and post-anaphase microtubules in the cytokinesis phase of the cell cycle , 2000, Current Biology.

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

[38]  S. Narumiya,et al.  Accumulation of GTP-bound RhoA during Cytokinesis and a Critical Role of ECT2 in This Accumulation* , 2000, The Journal of Biological Chemistry.

[39]  Gianluca Iaccarino,et al.  IMMERSED BOUNDARY METHODS , 2005 .

[40]  Junjie Chen,et al.  The Tandem BRCT Domains of Ect2 Are Required for Both Negative and Positive Regulation of Ect2 in Cytokinesis* , 2005, Journal of Biological Chemistry.

[41]  Kyung S. Lee,et al.  Inhibition of Cyclin-dependent Kinase 1 Induces Cytokinesis without Chromosome Segregation in an ECT2 and MgcRacGAP-dependent Manner* , 2005, Journal of Biological Chemistry.

[42]  M. Glotzer,et al.  Cytokinesis: welcome to the Rho zone. , 2005, Trends in cell biology.

[43]  G. Odell,et al.  Microtubules and mitotic cycle phase modulate spatiotemporal distributions of F-actin and myosin II in Drosophila syncytial blastoderm embryos. , 2000, Development.

[44]  Y. Hiramoto.  The mechanics and mechanism of cleavage in the sea-urchin egg. , 1968, Symposia of the Society for Experimental Biology.

[45]  R. Saint,et al.  A RhoGEF and Rho family GTPase-activating protein complex links the contractile ring to cortical microtubules at the onset of cytokinesis. , 2003, Developmental cell.

[46]  Marileen Dogterom,et al.  Dynamic instability of microtubules is regulated by force , 2003, The Journal of cell biology.

[47]  E. Holzbaur,et al.  Microtubule binding proteins CLIP‐170, EB1, and p150Glued form distinct plus‐end complexes , 2006, FEBS letters.

[48]  K. Kamijo,et al.  Dissecting the role of Rho-mediated signaling in contractile ring formation. , 2005, Molecular biology of the cell.