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  • Review Article
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Dynamic Microtubules Lead the Way for Spindle Positioning

Key Points

  • The mitotic spindle is positioned with respect to asymmetries in cellular polarity to ensure that the partitioning of genomes is coordinated with the partitioning of developmental determinants.

  • A small GTPase, CDC42, has a central role in establishing cell polarity and in promoting the localization of partitioning (PAR) proteins.

  • Centrosomes nucleate the microtubule network in interphase and mitosis, and provide essential cues for specification of the anterior–posterior axis in development.

  • Duplicated centrosomes are non-identical; the delivery of crucial components from one of the centrosomes to sites of polarized growth signals positional information to the mitotic spindle.

  • Microtubule plus-ends are active sites for the interchange of information between regions of polarized growth and the centrosome.

  • Proteins at microtubule plus-ends regulate microtubule dynamics as well as microtubule interactions with determinants of cell polarity.

  • Microtubules that are pushing against the plasma membrane, or being pulled at plus-end capture sites, provide the motive force for spindle positioning. Cellular geometry and the generation of asymmetric forces impose constraints on these activities.

  • Defects in spindle positioning are monitored by a signalling pathway (the spindle-positioning checkpoint) that functions to delay cytokinesis until proper spindle positioning is attained.

Abstract

Coordination between the asymmetric partitioning of cell-fate determinants and equal partitioning of genetic material is crucial to the generation of diverse cell types in a developing organism, and to the maintenance of genomic integrity. The emerging model is of a highly organized and dynamic cellular landscape, the form of which is defined by polarized signals within the cell. Cytoskeletal elements are necessary to generate this landscape and to provide motive forces for proper spindle positioning. These forces are generated by interactions between microtubules and the cell cortex.

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Figure 1: Asymmetric localization of Kar9 in Saccharomyces cerevisiae.
Figure 2: Stages involved in proper spindle positioning in Saccharomyces cerevisiae.
Figure 3: Balance of dynamic pushing and pulling forces in Saccharomyces cerevisiae.
Figure 4: Organelle positioning by microtubule pushing and pulling forces.

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References

  1. Horvitz, H. R. & Herskowitz, I. Mechanisms of asymmetric cell division: two Bs or not two Bs, that is the question. Cell 68, 237–255 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Inoue, S. & Salmon, E. D. Force generation by microtubule assembly/disassembly in mitosis and related movements. Mol. Biol. Cell 6, 1619–1640 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carvalho, P., Tirnauer, J. S. & Pellman, D. Surfing on microtubule ends. Trends Cell Biol. 13, 229–237 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Desai, A., Mitchison, T. J. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Howard, J. & Hyman, A. A. Dynamics and mechanics of the microtubule plus end. Nature 422, 753–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Holy, T. E. & Leibler, S. Dynamic instability of microtubules as an efficient way to search in space. Proc. Natl Acad. Sci. USA 91, 5682–5685 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Sagot, I., Rodal, A. A., Moseley, J., Goode, B. L. & Pellman, D. An actin nucleation mechanism mediated by Bni1 and profilin. Nature Cell Biol. 4, 626–631 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Pruyne, D. et al. Role of formins in actin assembly: nucleation and barbed-end association. Science 297, 612–615 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Severson, A. F., Baillie, D. L. & Bowerman, B. A formin homology protein and a profilin are required for cytokinesis and Arp2/3-independent assembly of cortical microfilaments in C. elegans. Curr. Biol. 12, 2066–2075 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Peng, J., Wallar, B. J., Flanders, A., Swiatek, P. J. & Alberts, A. S. Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42. Curr. Biol. 13, 534–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Palazzo, A. F. et al. Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536–1541 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Etienne-Manneville, S. & Hall, A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Garrard, S. M. et al. Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6. EMBO J. 22, 1125–1133 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ahringer, J. Control of cell polarity and mitotic spindle positioning in animal cells. Curr. Opin. Cell Biol. 15, 73–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Gonczy, P. Mechanisms of spindle positioning: focus on flies and worms. Trends Cell Biol. 12, 332–339 (2002).

    Article  PubMed  Google Scholar 

  16. O'Connell, K. F., Maxwell, K. N. & White, J. G. The spd-2 gene is required for polarization of the anteroposterior axis and formation of the sperm asters in the Caenorhabditis elegans zygote. Dev. Biol. 222, 55–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Wallenfang, M. R. & Seydoux, G. Polarization of the anterior–posterior axis of C. elegans is a microtubule-directed process. Nature 408, 89–92 (2000). Shows that microtubule-organizing centres provided by the sperm nucleus establish the anterior–posterior axis in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  18. Goldstein, B. & Hird, S. N. Specification of the anteroposterior axis in Caenorhabditis elegans. Development 122, 1467–1474 (1996).

    CAS  PubMed  Google Scholar 

  19. Gomes, J. E. et al. The maternal gene spn-4 encodes a predicted RRM protein required for mitotic spindle orientation and cell fate patterning in early C. elegans embryos. Development 128, 4301–4314 (2001).

    CAS  PubMed  Google Scholar 

  20. Maddox, P. et al. Microtubule dynamics from mating through the first zygotic division in the budding yeast Saccharomyces cerevisiae. J. Cell Biol. 144, 977–987 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Byers, B. & Goetsch, L. Duplication of spindle plaques and integration of the yeast cell cycle. Cold Spring Harb. Symp. Quant. Biol. 38, 123–131 (1974).

    Article  CAS  PubMed  Google Scholar 

  22. Byers, B. in The Molecular Biology of the Yeast Saccharomyces: Life Cycle and Inheritance (eds Strathern, J. N., Jones, E. W. & Broach, J. R) 59–96 (Cold Spring Harbor Laboratory, New York, 1981).

    Google Scholar 

  23. Rappleye, C. A., Tagawa, A., Lyczak, R., Bowerman, B. & Aroian, R. V. The anaphase-promoting complex and separin are required for embryonic anterior–posterior axis formation. Dev. Cell 2, 195–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Sadler, P. L. & Shakes, D. C. Anucleate Caenorhabditis elegans sperm can crawl, fertilize oocytes and direct anterior–posterior polarization of the 1-cell embryo. Development 127, 355–366 (2000).

    CAS  PubMed  Google Scholar 

  25. Cuenca, A. A., Schetter, A., Aceto, D., Kemphues, K. & Seydoux, G. Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases. Development 130, 1255–1265 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Behrens, R. & Nurse, P. Roles of fission yeast tea1p in the localization of polarity factors and in organizing the microtubular cytoskeleton. J. Cell Biol. 157, 783–793 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Browning, H., Hackney, D. D. & Nurse, P. Targeted movement of cell end factors in fission yeast. Nature Cell Biol. 5, 812–818 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Mata, J. & Nurse, P. tea1 and the microtubular cytoskeleton are important for generating global spatial order within the fission yeast cell. Cell 89, 939–949 (1997). This paper identified the first tea mutant, tea1 . The Tea1 protein is required to restrict cell growth to the cylindrical ends of S. pombe.

    Article  CAS  PubMed  Google Scholar 

  29. Browning, H. et al. Tea2p is a kinesin-like protein required to generate polarized growth in fission yeast. J. Cell Biol. 151, 15–28 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rogers, S. L., Rogers, G. C., Sharp, D. J. & Vale, R. D. Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle. J. Cell Biol. 158, 873–884 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tirnauer, J. S., O'Toole, E. O., Berrueta, L., Bierer, B. E. & Pellman, D. Yeast Bim1p promotes the G1-specific dynamics of microtubules. J. Cell Biol. 145, 993–1007 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Beinhauer, J. D., Hagan, I. M., Hegemann, J. H. & Fleig, U. Mal3, the fission yeast homologue of the human APC-interacting protein EB-1 is required for microtubule integrity and the maintenance of cell form. J. Cell Biol. 139, 717–728 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brunner, D. & Nurse, P. CLIP170-like tip1p spatially organizes microtubular dynamics in fission yeast. Cell 102, 695–704 (2000).

    Article  CAS  Google Scholar 

  34. Snaith, H. A. & Sawin, K. E. Fission yeast mod5p regulates polarized growth through anchoring of tea1p at cell tips. Nature 423, 647–651 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Glynn, J. M., Lustig, R. J., Berlin, A. & Chang, F. Role of bud6p and tea1p in the interaction between actin and microtubules for the establishment of cell polarity in fission yeast. Curr. Biol. 11, 836–845 (2001). Shows that the microtubule plus-end-binding protein Tea1 interacts with Bud6 (an actin-associated factor). These results provide evidence of a direct mechanistic interaction between the actin and microtubule cytoskeletons.

    Article  CAS  PubMed  Google Scholar 

  36. Kochanski, R. S. & Borisy, G. G. Mode of centriole duplication and distribution. J. Cell Biol. 110, 1599–1605 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Piel, M., Meyer, P., Khodjakov, A., Rieder, C. L. & Bornens, M. The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J. Cell Biol. 149, 317–330 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Augustin, A. et al. PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J. Cell Sci. 116, 1551–1562 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Kirkham, M., Muller-Reichert, T., Oegema, K., Grill, S. & Hyman, A. A. SAS-4 is a C. elegans centriolar protein that controls centrosome size. Cell 112, 575–587 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Leidel, S. & Gonczy, P. SAS-4 is essential for centrosome duplication in C. elegans and is recruited to daughter centrioles once per cell cycle. Dev. Cell 4, 431–439 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Pereira, G., Tanaka, T. U., Nasmyth, K. & Schiebel, E. Modes of spindle pole body inheritance and segregation of the Bfa1p–Bub2p checkpoint protein complex. EMBO J. 20, 6359–6370 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yoder, T. J., Pearson, C. G., Bloom, K. & Davis, T. N. The Saccharomyces cerevisiae spindle pole body is a dynamic structure. Mol. Biol. Cell 14, 3494–3505 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yeh, E., Skibbens, R. V., Cheng, J. W., Salmon, E. D. & Bloom, K. Spindle dynamics and cell cycle regulation of dynein in the budding yeast, Saccharomyces cerevisiae. J. Cell Biol. 130, 687–700 (1995). The first live-cell, differential-interference contrast-microscopy study of yeast mitosis. Shows that the microtubule-based motor dynein is essential for nuclear migration. Also shows that there are mechanisms by which cells prevent cytokinesis until genome partitioning is complete.

    Article  CAS  PubMed  Google Scholar 

  44. Shaw, S. L., Yeh, E., Maddox, P., Salmon, E. D. & Bloom, K. Astral microtubule dynamics in yeast: a microtubule-based searching mechanism for spindle orientation and nuclear migration into the bud. J. Cell Biol. 139, 985–994 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Segal, M. et al. Coordinated spindle assembly and orientation requires Clb5p-dependent kinase in budding yeast. J. Cell Biol. 148, 441–452 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bienz, M. Spindles cotton on to junctions, APC and EB1. Nature Cell Biol. 3, E67–E68 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Zumbrunn, J., Kinoshita, K., Hyman, A. A. & Nathke, I. S. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation. Curr. Biol. 11, 44–49 (2001). Shows that the adenomatous polyposis coli (APC) protein binds and stabilizes microtubule plus-ends.

    Article  CAS  PubMed  Google Scholar 

  48. Etienne-Manneville, S. & Hall, A. Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003). Identification of the downstream effectors of CDC42 that bring about cell polarity. Shows that CDC42-dependent phosphorylation of GSK3β promotes the interaction of microtubule plus-ends with the APC protein.

    Article  CAS  PubMed  Google Scholar 

  49. Liakopoulos, D., Kusch, J., Grava, S., Vogel, J. & Barral, Y. Asymmetric loading of Kar9 onto spindle poles and microtubules ensures proper spindle alignment. Cell 112, 561–574 (2003). Shows that the asymmetric localization of Kar9 to the spindle pole that is destined for the bud in S. cerevisiae is regulated by cyclin–Cdk.

    Article  CAS  PubMed  Google Scholar 

  50. Schuyler, S. C. & Pellman, D. Microtubule 'plus-end-tracking proteins': the end is just the beginning. Cell 105, 421–424 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Duncan, J. E. & Warrior, R. The cytoplasmic dynein and kinesin motors have interdependent roles in patterning the Drosophila oocyte. Curr. Biol. 12, 1982–1991 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Brendza, R. P., Serbus, L. R., Saxton, W. M. & Duffy, J. B. Posterior localization of dynein and dorsal–ventral axis formation depend on kinesin in Drosophila oocytes. Curr. Biol. 12, 1541–1545 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sheeman, B. et al. Determinants of S. cerevisiae dynein localization and activation: implications for the mechanism of spindle positioning. Curr. Biol. 13, 364–372 (2003). Shows that cytoplasmic dynein is required for the fidelity of spindle positioning in yeast. The authors demonstrate that dynein is delivered to the cell cortex on the plus-ends of polymerized microtubules.

    Article  CAS  PubMed  Google Scholar 

  54. Vaughan, P. S., Miura, P., Henderson, M., Byrne, B. & Vaughan, K. T. A role for regulated binding of p150Glued to microtubule plus ends in organelle transport. J. Cell Biol. 158, 305–319 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Maekawa, H., Usui, T., Knop, M. & Schiebel, E. Yeast Cdk1 translocates to the plus end of cytoplasmic microtubules to regulate bud cortex interactions. EMBO J. 22, 438–449 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lee, L. et al. Positioning of the mitotic spindle by a cortical-microtubule capture mechanism. Science 287, 2260–2262 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Korinek, W. S., Copeland, M. J., Chaudhuri, A. & Chant, J. Molecular linkage underlying microtubule orientation toward cortical sites in yeast. Science 287, 2257–2259 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Meluh, P. B. & Rose, M. D. KAR3, a kinesin-related gene required for yeast nuclear fusion. Cell 60, 1029–1041 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Maddox, P. S., Stemple, J. K., Satterwhite, L., Salmon, E. D. & Bloom, K. The minus end-directed motor Kar3 is required for coupling dynamic microtubule plus ends to the cortical shmoo tip in budding yeast. Curr. Biol. 13, 1423–1428 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Miller, R. K., Cheng, S. C. & Rose, M. D. Bim1p/Yeb1p mediates the Kar9p-dependent cortical attachment of cytoplasmic microtubules. Mol. Biol. Cell 11, 2949–2959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yin, H., Pruyne, D., Huffaker, T. C. & Bretscher, A. Myosin V orientates the mitotic spindle in yeast. Nature 406, 1013–1015 (2000). Showed that class-V myosin links the actin cytoskeleton to the microtubule cytoskeleton via Kar9 for spindle positioning.

    Article  CAS  PubMed  Google Scholar 

  62. Tirnauer, J. S., Canman, J. C., Salmon, E. D. & Mitchison, T. J. EB1 targets to kinetochores with attached, polymerizing microtubules. Mol. Biol. Cell 13, 4308–4316 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Endow, S. A. et al. Yeast Kar3 is a minus-end microtubule motor protein that destabilizes microtubules preferentially at the minus ends. EMBO J. 13, 2708–2713 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lombillo, V. A., Stewart, R. J. & McIntosh, J. R. Minus-end-directed motion of kinesin-coated microspheres driven by microtubule depolymerization. Nature 373, 161–164 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Hunter, A. W. et al. The kinesin-related protein MCAK is a microtubule depolymerase that forms an ATP-hydrolyzing complex at microtubule ends. Mol. Cell 11, 445–457 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Desai, A., Verma, S., Mitchison, T. J. & Walczak, C. E. KinI kinesins are microtubule-destabilizing enzymes. Cell 96, 69–78 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Cassimeris, L. The oncoprotein 18/stathmin family of microtubule destabilizers. Curr. Opin. Cell Biol. 14, 18–24 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Gard, D. L. & Kirschner, M. W. A microtubule-associated protein from Xenopus eggs that specifically promote assembly at the plus-end. J. Cell Biol. 105, 2203–2215 (1987).

    Article  CAS  PubMed  Google Scholar 

  69. Vasquez, R. J., Gard, D. L. & Cassimeris, L. XMAP from Xenopus eggs promotes rapid plus end assembly of microtubules and rapid microtubule polymer turnover. J. Cell Biol. 127, 985–993 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Popov, A. V. et al. XMAP215 regulates microtubule dynamics through two distinct domains. EMBO J. 20, 397–410 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shirasu-Hiza, M., Coughlin, P. & Mitchison, T. Identification of XMAP215 as a microtubule-destabilizing factor in Xenopus egg extract by biochemical purification. J. Cell Biol. 161, 349–358 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. van Breugal, M., Drechsel, D. & Hyman, A. Stu2p, the budding yeast member of the conserved Dis1/XMAP215 family of microtubule-associated proteins is a plus end-binding microtubule destabilizer. J. Cell Biol. 161, 359–369 (2003).

    Article  CAS  Google Scholar 

  73. Severin, F., Habermann, B., Huffaker, T. & Hyman, T. Stu2 promotes mitotic spindle elongation in anaphase. J. Cell Biol. 153, 435–442 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kinoshita, K., Habermann, B. & Hyman, A. A. XMAP215: a key component of the dynamic microtubule cytoskeleton. Trends Cell Biol. 12, 267–273 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Bellanger, J. M. & Gonczy, P. TAC-1 and ZYG-9 form a complex that promotes microtubule assembly in C. elegans embryos. Curr. Biol. 13, 1488–1498 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Le Bot, N., Tsai, M. C., Andrews, R. K. & Ahringer, J. TAC-1, a regulator of microtubule length in the C. elegans embryo. Curr. Biol. 13, 1499–1505 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Srayko, M., Quintin, S., Schwager, A. & Hyman, A. A. Caenorhabditis elegans TAC-1 and ZYG-9 form a complex that is essential for long astral and spindle microtubules. Curr. Biol. 13, 1506–1511 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Kosco, K. A. et al. Control of microtubule dynamics by Stu2p is essential for spindle orientation and metaphase chromosome alignment in yeast. Mol. Biol. Cell 12, 2870–2880 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gupta, M. L. Jr. et al. β-Tubulin C354 mutations that severely decrease microtubule dynamics do not prevent nuclear migration in yeast. Mol. Biol. Cell 13, 2919–2932 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Labbe, J. C., Maddox, P. S., Salmon, E. D. & Goldstein, B. PAR proteins regulate microtubule dynamics at the cell cortex in C. elegans. Curr. Biol. 13, 707–714 (2003). By developing new imaging techniques, these investigators demonstrated that, during spindle displacement in one-celled C. elegans embryos, microtubules are more dynamic at the posterior than at the anterior cortex.

    Article  CAS  PubMed  Google Scholar 

  81. Wright, A. J. & Hunter, C. P. Mutations in a β-tubulin disrupt spindle orientation and microtubule dynamics in the early Caenorhabditis elegans embryo. Mol. Biol. Cell 14, 4512–4525 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Matthews, L. R., Carter, P., Thierry-Mieg, D. & Kemphues, K. ZYG-9, a Caenorhabditis elegans protein required for microtubule organization and function, is a component of meiotic and mitotic spindle poles. J. Cell Biol. 141, 1159–1168 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Miller, K. G. & Rand, J. B. A role for RIC-8 (Synembryn) and GOA-1 (Goα) in regulating a subset of centrosome movements during early embryogenesis in Caenorhabditis elegans. Genetics 156, 1649–1660 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gotta, M. & Ahringer, J. Distinct roles for Gα and Gβγ in regulating spindle position and orientation in Caenorhabditis elegans embryos. Nature Cell Biol. 3, 297–300 (2001). Showed that different subunits of heterotrimeric G-proteins are involved in distinct microtubule-dependent centrosome and spindle processes.

    Article  CAS  PubMed  Google Scholar 

  85. Gonczy, P. et al. Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome III. Nature 408, 331–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Colombo, K. et al. Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos. Science 300, 1957–1961 (2003). Revealed that net pulling forces on microtubules depend on the activity of a Gα protein at the cellular cortex.

    Article  CAS  PubMed  Google Scholar 

  87. Srinivasan, D. G., Fisk, R. M., Xu, H. & van den Heuvel, S. A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C. elegans. Genes Dev. 17, 1225–1239 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gotta, M., Dong, Y., Peterson, Y. K., Lanier, S. M. & Ahringer, J. Asymmetrically distributed C. elegans homologs of AGS3/PINS control spindle position in the early embryo. Curr. Biol. 13, 1029–1037 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Schaefer, M., Petronczki, M., Dorner, D., Forte, M. & Knoblich, J. A. Heterotrimeric G proteins direct two modes of asymmetric cell division in the Drosophila nervous system. Cell 107, 183–194 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Grill, S. W., Gonczy, P., Stelzer, E. H. & Hyman, A. A. Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo. Nature 409, 630–633 (2001). Using an ultraviolet laser beam, these investigators severed the central spindle and showed that pulling forces are stronger in the posterior half of the C. elegans embryo.

    Article  CAS  PubMed  Google Scholar 

  91. Grill, S. W., Howard, J., Schaffer, E., Stelzer, E. H. & Hyman, A. A. The distribution of active force generators controls mitotic spindle position. Science 301, 518–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Mitchison, T. J. & Salmon, E. D. Mitosis: a history of division. Nature Cell Biol. 3, E17–E21 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Mogilner, A. & Oster, G. Polymer motors: pushing out the front and pulling up the back. Curr. Biol. 13, R721–R733 (2003). A mathematical discourse on how forces can be generated by polymer growth and shortening, for instance in the case of microtubules.

    Article  CAS  PubMed  Google Scholar 

  94. Holy, T. E., Dogterom, M., Yurke, B. & Leibler, S. Assembly and positioning of microtubule asters in microfabricated chambers. Proc. Natl Acad. Sci. USA 94, 6228–6231 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Waterman-Storer, C. M. & Salmon, E. D. Actomyosin-based retrograde flow of microtubules in the lamella of migrating epithelial cells influences microtubule dynamic instability and turnover and is associated with microtubule breakage and treadmilling. J. Cell Biol. 139, 417–434 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Faivre-Moskalenko, C. & Dogterom, M. Dynamics of microtubule asters in microfabricated chambers: the role of catastrophes. Proc. Natl Acad. Sci. USA 99, 16788–16793 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Janson, M. E., de Dood, M. E. & Dogterom, M. Dynamic instability of microtubules is regulated by force. J. Cell Biol. 161, 1029–1034 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tran, P. T., Marsh, L., Doye, V., Inoue, S. & Chang, F. A mechanism for nuclear positioning in fission yeast based on microtubule pushing. J. Cell Biol. 153, 397–411 (2001). Imaging of microtubule pushing forces in S. pombe , and postulation, based also on modelling, that pushing forces contribute to spindle positioning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Carminati, J. L. & Stearns, T. Microtubules orient the mitotic spindle in yeast through dynein-dependent interactions with the cell cortex. J. Cell Biol. 138, 629–641 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Adames, N. R. & Cooper, J. A. Microtubule interactions with the cell cortex causing nuclear movements in Saccharomyces cerevisiae. J. Cell Biol. 149, 1–13 (2000).

    Article  Google Scholar 

  101. Yeh, E. et al. Dynamic positioning of mitotic spindles in yeast: role of microtubule motors and cortical determinants. Mol. Biol. Cell 11, 3949–3961 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hwang, E., Kusch, J., Barral, Y. & Huffaker, T. C. Spindle orientation in Saccharomyces cerevisiae depends on the transport of microtubule ends along polarized actin cables. J. Cell Biol. 161, 483–488 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kormanec, J., Schaaff-Gerstenschlager, I., Zimmermann, F. K., Perecko, D. & Kuntzel, H. Nuclear migration in Saccharomyces cerevisiae is controlled by the highly repetitive 313 kDa NUM1 protein. Mol. Gen. Genet. 230, 277–287 (1991).

    Article  CAS  PubMed  Google Scholar 

  104. Farkasovsky, M. & Kuntzel, H. Cortical Num1p interacts with the dynein intermediate chain Pac11p and cytoplasmic microtubules in budding yeast. J. Cell Biol. 152, 251–262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Heil-Chapdelaine, R. A., Oberle, J. R. & Cooper, J. A. The cortical protein Num1p is essential for dynein-dependent interactions of microtubules with the cortex. J. Cell Biol. 151, 1337–1344 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Rieder, C. L. & Alexander, S. P. Kinetochores are transported poleward along a single astral microtubule during chromosome attachment to the spindle in newt lung cells. J. Cell Biol. 110, 81–95 (1990).

    Article  CAS  PubMed  Google Scholar 

  107. Merdes, A. & De May, J. The mechanism of kinetochore-spindle attachment and polewards movement analyzed in PtK2 cells at the prophase-prometaphase transition. Eur. J. Cell Biol. 53, 313–325 (1990).

    CAS  PubMed  Google Scholar 

  108. Tsou, M. F., Ku, W., Hayashi, A. & Rose, L. S. PAR-dependent and geometry-dependent mechanisms of spindle positioning. J. Cell Biol. 160, 845–855 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kapoor, T. M. & Compton, D. A. Searching for the middle ground: mechanisms of chromosome alignment during mitosis. J. Cell Biol. 157, 551–556 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shaw, S. L. et al. Nuclear and spindle dynamics in budding yeast. Mol. Biol. Cell 9, 1627–1631 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Smeets, M. F. & Segal, M. Spindle polarity in S. cerevisiae: MEN can tell. Cell Cycle 1, 308–311 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Bardin, A. J. & Amon, A. MEN and SIN: what's the difference? Nature Rev. Mol. Cell Biol. 2, 815–826 (2001).

    Article  CAS  Google Scholar 

  113. Adames, N. R., Oberle, J. R. & Cooper, J. A. The surveillance mechanism of the spindle position checkpoint in yeast. J. Cell Biol. 153, 159–168 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bardin, A. J., Visintin, R. & Amon, A. A mechanism for coupling exit from mitosis to partitioning of the nucleus. Cell 102, 21–31 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Pereira, G., Hofken, T., Grindlay, J., Manson, C. & Schiebel, E. The Bub2p spindle checkpoint links nuclear migration with mitotic exit. Mol. Cell 6, 1–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Visintin, R. & Amon, A. Regulation of the mitotic exit protein kinases Cdc15 and Dbf2. Mol. Biol. Cell 12, 2961–2974 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hoyt, M. A. Exit from mitosis: spindle pole power. Cell 102, 267–270 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Molk, J. N. et al. The differential roles of budding yeast Tem1p, Cdc15p, and Bub2p protein dynamics in mitotic exit. Mol. Biol. Cell 15, 1519–1532 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pereira, G., Manson, C., Grindlay, J. & Schiebel, E. Regulation of the Bfa1p–Bub2p complex at spindle pole bodies by the cell cycle phosphatase Cdc14p. J. Cell Biol. 157, 367–379 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Plant, P. J. et al. A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl. Nature Cell Biol. 5, 301–308 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Shi, S. H., Jan, L. Y. & Jan, Y. N. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Mitchison, T. & Kirschner, M. Dynamic instability of microtubule growth. Nature 312, 237–242 (1984).

    Article  CAS  PubMed  Google Scholar 

  123. Caplow, M., Ruhlen, R. L. & Shanks, J. The free energy for hydrolysis of a microtubule-bound nucleotide triphosphate is near zero: all of the free energy for hydrolysis is stored in the microtubule lattice. J. Cell Biol. 127, 779–788 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Hyman, A. A., Chretien, D., Arnal, I. & Wade, R. H. Structural changes accompanying GTP hydrolysis in microtubules: information from a slowly hydrolyzable analogue guanylyl-(α,β)-methylene-diphosphonate. J. Cell Biol. 128, 117–125 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Tran, P. T., Walker, R. A. & Salmon, E. D. A metastable intermediate state of microtubule dynamic instability that differs significantly between plus and minus ends. J. Cell Biol. 138, 105–117 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Segal, M., Bloom, K. & Reed, S. I. Kar9p-independent microtubule capture at Bud6p cortical sites primes spindle polarity before bud emergence in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 4141–4155 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kusch, J., Meyer, A., Snyder, M. P. & Barral, Y. Microtubule capture by the cleavage apparatus is required for proper spindle positioning in yeast. Genes Dev. 16, 1627–1639 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. C. Labbé, J. Deluca and B. Goldstein for their thoughtful and careful comments on this review. We also thank the reviewers for their helpful input. This work was supported by the National Institutes of Heath.

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Correspondence to Kerry Bloom.

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DATABASES

Saccharomyces genome database

Bim1

Bfa1

Cdc28

Clb4

Kar9

Myo2

num1

Stu2

Tem1

Schizosaccharomyces pombe gene database

Mod5

Mal3

Tea1

Tea2

Tip1

Swiss-Prot

aPKC

CDC42

p150GLUED

PAR6

PARP3

ZYG-9

Glossary

CENTROSOME

Also called the microtubule-organizing centre (MTOC) or spindle pole, this structure nucleates microtubules and is important for signalling processes.

SPINDLE

A bipolar microtubule array with microtubules organized from each spindle pole. The spindle is composed of polar, kinetochore and astral microtubules.

ANAPHASE

The period of mitosis during which duplicated chromosomes are segregated. In anaphase A, chromosomes move towards centrosomes; in anaphase B, the centrosomes are segregated.

CYTOKINESIS

The separation of a cell into two, marked by ingression of the cleavage 'furrow' between two segregated masses of genomic DNA.

SMALL GTPases

Diverse cellular regulatory proteins that are controlled by the nature of bound nucleotide (active when bound to GTP; inactive when bound to GDP).

TIGHT JUNCTION

A seal between adjacent epithelial cells, just beneath their apical surface. PAR proteins migrate to tight junctions in mammalian cells.

MICROTUBULE-ORGANIZING CENTRE

(MTOC). Also called the centrosome or spindle-pole body, this structure nucleates and organizes microtubules.

P1

The first cell division in C. elegans produces a large anterior blastemere, AB, a blastomere and a smaller posterior blastomere, P1.

SPINDLE-POLE BODY

The budding-yeast equivalent of the centrosome/spindle pole or MTOC. This structure, which is embedded in the nuclear envelope, nucleates both cytoplasmic and nuclear microtubules.

ASTER

An organized microtubule array, with the microtubule minus-ends focused at a point or centrosome, and the plus-ends emanating outwards.

CHROMATIN

Chromosomal DNA and associated proteins.

PLUS-END

The predominantly dynamic end of a microtubule, with β-tubulin exposed.

METAZOAN

Refers to the kingdom Animalia (animals) that comprises roughly 35 phyla of multicellular organisms.

CENTRIOLE

A short, barrel-like array of microtubules that organizes the centrosome and contributes to cytokinesis and cell-cycle progression.

TUBULIN

The basic subunit of microtubules. Tubulin comes in two forms, α- and β-tubulin, which form heterodimers that make up microtubules.

GTPase-ACTIVATING PROTEIN

(GAP). A protein that inactivates small GTP-binding proteins, such as RAS-family members, by increasing their rate of GTP hydrolysis.

ADENOMATOUS POLYPOSIS COLI

(APC). A protein that is mutated in many colorectal cancers. APC binds to microtubules and the microtubule regulator EB1.

CYCLINS

A family of binding partners for the main cell-cycle regulators, cyclin-dependent kinases. Cyclins are completely degraded and newly synthesized for progression through each cell cycle.

MINUS-END

The predominantly stable end of a microtubule, which has exposed α-tubulin.

KINETOCHORE

A protein complex that provides a link between centromeric DNA and microtubules.

KARYOGAMY

The process in which two haploid nuclei come together and fuse to form a diploid nucleus during mating in S. cerevisiae.

CATASTROPHE

The transition from microtubule growth to shortening.

PROTOFILAMENT

Tubulin dimers aligned end-to-end make up protofilaments. Several protofilaments (usually 13) are organized into a tubular structure to form microtubules.

ASTRAL MICROTUBULE

A microtubule that is nucleated at the spindle pole and grows outwards towards the cell cortex; it is involved in spindle positioning.

FORMINS

A family of proteins that contain a formin homology-2 (FH2) domain. They are capable of promoting actin assembly.

RNA INTERFERENCE

(RNAi). A method to block the translation of RNA and thereby 'knock-down' the levels of specific proteins.

GUANINE NUCLEOTIDE-DISSOCIATION INHIBITOR

(GDI). A protein that inhibits the dissociation of GDP and therefore its replacement by GTP in a small GTPase, thereby maintaining the GTPase in an inactive state.

N-MYRISTOYLATION

The chemical addition of the fatty acid myristate to the amino terminus of a protein, which enables that protein to become localized to a membrane.

PLECKSTRIN-HOMOLOGY DOMAIN

A protein domain that is typically made up of 100 amino-acid residues, and is found in many proteins that are involved in intracellular signalling. Named after pleckstrin, the main substrate of protein kinase C in platelets.

METAPHASE PLATE

During mitosis, chromosomes align at an equatorial plane between the two spindle poles, which is defined as the metaphase plate.

MITOTIC EXIT NETWORK

(MEN). A signalling cascade that regulates the timing of spindle disassembly and cytokinesis.

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Pearson, C., Bloom, K. Dynamic Microtubules Lead the Way for Spindle Positioning. Nat Rev Mol Cell Biol 5, 481–492 (2004). https://doi.org/10.1038/nrm1402

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