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Mitosis: a history of division
Author: T. J. Mitchison
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"� 2001 Macmillan Magazines Ltd historical perspective NATURE CELL BIOLOGY VOL 3 JANUARY 2001 http://cellbio.nature.com E17 Mitosis: a history of division T. J. Mitchison and E. D. Salmon Mitosis has been studied since the early 1880s, to the extent that we now have a detailed, but still incomplete, description of spindle dynamics and mechanics, a sense of potential mechanochemical and regulatory mechanisms at a molecular level, and a long list of mitotic proteins. Here we pres- ent a personal view of how far we have come, and where we need to go to fully understand the mechanisms involved in mitosis. W alther Flemming 1 originally coined the term mitosis in the early 1880s from the Greek word for thread, relfecting the shape of mitotic chromo- somes. The basic mechanics of mitosis were described by live imaging from the 1920s to the 1950s and we now have a detailed, although incomplete, overall picture of mitosis. For scholarly reviews, see refs 2?12 and page E27 of this issue. Chromatin dynamics were well described by early cytologists, partly because chromatin binds to dye molecules so well, hence its name. They described condensation of nuclear material into chro- mosomes in which the paired sister chro- matids are visible (Fig. 1a), and longtitudi- nal splitting between sister chromatids at anaphase 1,2 . We now understand packaging of DNA into nucleosomes and chromatin fibres fairly well, although how these fibres assemble into mitotic chromosomes remains unknown. The early images revealed, in retrospect, that condensation sorts sister DNA strands into paired chro- matids, and that these remain cohered until anaphase. A significant breakthrough in understanding the ?glue? that promotes sis- ter-chromatid cohesion was the identifica- tion of the cohesin complex, one subunit of which is proteolyzed to trigger sister-chro- matid separation in yeast mitosis and meio- sis 13 . However, mysteries remain, particu- larly in the relationship between condensa- tion and cohesion. During prophase in ver- tebrates a different complex, condensin, is recruited to chromatin, where it is thought somehow to promote condensation 14 (Fig. 1b). Most of the cohesin is released during condensation, although a small fraction remains between the centromeres, where it presumably promotes cohesion 15 (Fig. 1c). Although condensation and cohesion seem to be mechanistically very different, cohesin and condensin and are thought to share some biochemical function, as both contain heterodimeric pairs of SMC polypeptides 14 . Elucidating this shared function may be one key to understanding chromatin dynamics in mitosis. The shape of the mitotic spindle, together with evidence for filamentous organization, was described by early cytologists 1,2 (Fig.1), and forces acting parallel to the spindle axis were evident from fixed images and early time-lapse movies of mitosis 2,3,6,16?18 (Fig. 2a). Conclusive evidence that spindles are made of filaments running parallel to the direction of chromosome movement came from polarization microscopy in the early 1950s (ref. 7, Supplementary Information Fig. S1a). The rapid, reversible response of spindle filaments to perturbation led to the proposal that polymerization dynamics might drive chromosome movement 7 ,a model that is still relevant (Fig. 2b). Introduction of gluraraldehyde fixation subsequently allowed electron-microscopic observation of spindle microtubules and kinetochores in the early 1960s (refs 6, 19). Tubulin was identified in the late 1960s by its prevalence in flagella and ability to bind to radioactive colchicine 5,20,21 , and polymer- ization of brain tubulin in vitro was described in 1972 (ref. 22). Tubulin bio- chemistry gave rise to two models of poly- merization dynamics driven by GTP hydrolysis ? treadmilling 23 and dynamic instability 24 . Treadmilling was inferred from GTP incorporation at steady state that was, in retrospect, probably due to dynamic instability 25 ; treadmilling of pure tubulin has not been directly observed. Photobleaching of fluorescein?tubulin first revealed that spindle microtubules turn over very rapidly at steady state 26,27 . Fast turnover was confirmed by injection of biotin?tubu- lin 28 and fluorescence photoactivation (Fig. 3c). Dynamic instability of microtubule plus ends is now thought to account for the majority of fast subunit turnover in animal Figure 1 Old and new views of mitotic chro- mosomes. a, Metaphase salamander cell drawn by Walther Flemming from a stained preparation (adapted from Views of the Cell, J. Gall, ASCB, Bethseda, Maryland; 1996). Note the ?thread-like? paired sister chromatids, joined along their lengths, and the spindle fibres. b, Replicated mitotic chromosome assembled in Xenopus egg extract and stained for DNA (red) and a subunit of the condensin complex (green). Note that condensin, which has a key function in chromatin condensation 14 , is targeted to a subset of DNA. (Image courtesy of T. Hirano, Cold Spring Harbor Laboratory, New York.) c, Mitotic chromosome from a nocodazole- arrested human cell stained for DNA (blue), kinetochores (green) and a subunit of the cohesin complex (SCC1, red). Note that cohesin is present between the cen- tromeres where sister chromatids are still joined. Cohesin is thought to hold sister chromatids together until anaphase 13,15 . (Image courtesy of S. Hauf and J-M. Peters, IMP, Vienna, Austria.) f focus on cell division � 2001 Macmillan Magazines Ltd historical perspective NATURE CELL BIOLOGY VOL 3 JANUARY 2001 http://cellbio.nature.comE18 ab cd af + + + + + + ? ? ? ? Figure 2 Evolution of ideas for spindle organization and force generation. a, Ostergren?s view in the late 1940s, as dis- cussed refs 6, 18. The image represents spindle in an insect spermatocyte. The forces acting on chromosomes (arrows) were inferred from chromsome stretching and time-lapse imaging of movement. Ostergren argued that metaphase align- ment was due to equalization of pulling forces when the chromosome was cen- tered on the metaphase plate. (Image adapted from ref. 6.) b, Inoue?s view in the mid 1960s (ref. 7). Protein-assembly dynamics are central to force production, but the structural details are unclear. Later, Inoue concluded on the basis of experiments (Supplementary Information Fig. S1a) that tubulin must be polymerized at kinetochores during metaphase, and depolymerized near the poles 56 . (Image adapted from ref. 6.) c, The model pro- posed by McIntosh et al. 44 in 1969, which explicitly invokes microtubule polarity and motor proteins. Horizontal arrows indicate microtubules and their polarity; short diag- onal arrows represent putative mechanochemical enzymes. The predicted microtubule polarity is incorrect, but this model was very important in highlighting the importance of polarity and in stimulat- ing the search for motor proteins involved in mitosis. d, Margolis and Wilson?s 1981 treadmilling model 59 . Arrows show sites of polymerization at kinetochores and free microtubule plus ends, and depolymeriza- tion at poles; they also indicate micro- tubule polarity. This model combined knowledge of tubulin biochemistry 57 and spindle-microtubule polarity 37 (polarity is indicated with plus and minus signs) and results indicating poleward flux (Supplementary Information Fig. S1a). It predicted poleward flux and postulated functions for dynamics and motors that are still relevant. Whether treadmilling driven by GTP hydrolysis on tubulin has a role in poleward flux remains to be determined. e, Current model for polymerization dynamics of kinetochore microtubules, showing the role of dynamics at kineto- chore and poles in vertebrate tissue-cul- ture cells. The red mark represents a fidu- ciary mark such as those shown in Fig. 4c, d. Depolymerization at kinetochores, which was discovered by marking experi- ments 28,38 , now has a key role in chromo- some movement. Poleward flux, which has now been directly observed 40,41 , is also important. f, Current, motor-centric model that emphasizes the role of Eg5 (red) and dynein (yellow) in organizing the spin- dle 12,47 . Kinetochores (orange) are shown moving polewards through the action of a motor (also orange) that may be dynein or an unknown motor protein 11 . Another motor possibly involved in chromosome movement is attached to chromosome arms (blue). The minus ends of spindle microtubules are shown detached from the centrosomes to allow flux. � 2001 Macmillan Magazines Ltd historical perspective NATURE CELL BIOLOGY VOL 3 JANUARY 2001 http://cellbio.nature.com E19 spindles 9 , although the complete life histo- ry of spindle microtubules is not known. Photobleaching of tubulin tagged with green fluorescent protein allows turnover to be probed in yeast 29,30 (See Supplementary Information Fig. S1b), where genetics will help to reveal mecha- nism. To understand spindle mechanics, it has long been clear that we need to measure the forces acting in the spindle, and also to determine the arrangement and dynamics of the microtubules that are involved in force production. Direct force measure- ment using microneedles revealed that large forces pull chromosomes towards the poles during anaphase A 31 , indicating, alongside other micromanipulation data 32 , that the rate of chromosome movement may be limited by a velocity governor, which may be distinct from the force gener- ator(s). A velocity governor in the overlap zone may also limit the rate of spindle expansion (anaphase B) in some systems 33 . The static arrangement of microtubules in animal and yeast spindles is now largely understood as a result of painstaking elec- tron-microscopic analysis 34?36 , including the structural polarity of microtubules 37 , which is key to modern mechanical models. Our understanding of dynamics in relation to mechanics is still evolving. Progress has been made in part through development of successively improved methods for making fiduciary marks on microtubules (Fig. 3). We now think that in simple spindles, such as those in yeast, microtubules polymerize at kinetochores when chromosomes move away from poles, and depolymerize there when they move polewards 29,30 . In larger, more complex animal spindles, these kine- tochore-based mechanisms still operate 28,38 , but superimposed on them is a second mechanism for poleward movement in which microtubules flux polewards and depolymerize at poles 39?41 . Prometaphase congression and anaphase B movements have been less studied by microtubule marking. Anaphase B in yeast and diatoms involves antiparallel sliding 29,30,35,36 , although how this is powered and regulated is poorly understood. Congression is a par- ticularly interesting problem, as balancing chromosomes at the metaphase plate requires position-dependent forces (Fig. 2a). Two models dominate current discus- sion ? the force per unit length that pulls on kinetochore fibres 18,42 , and opposition of kinetochore pulling by pushing on chromo- some arms from astral ejection forces 11,43 . Strong arguments exist for both models in different systems, and one model may not apply to all spindles. Overall, we still have a long way to go to understand spindle mechanics, and specific mechanisms may not be suitable for generalization. Progress will require better ways of imaging dynam- ics, in conjunction with new methods for Pre-irradiation 2 min 11 min 16 min Pre-bleach 10 s 152 s 362 s a c d e b Figure 3 Evolution of microtubule-marking technology. a, Area of reduced birefrin- gence produced by locally ablating micro- tubules in an insect spermatocyte with an ultraviolet microbeam 39 . Images were obtained before irradiation and at the indi- cated times after. The spindle is about 40 mm long. (Adapted from ref. 56.) b, Polymerization of biotin-labelled tubulin at a kinetochore in a PtK 2 cell (adapted from ref. 28). This cell was fixed 120 s after microinjection. A short segment of biotin- labelled microtubule, visualized with gold particles, has polymerized at the kineto- chore; the labelled segments disappeared in anaphase. c, Photobleaching of rho- damine?tubulin in an LLC-PK1 cell during anaphase (adapted from ref. 38). As the chromosomes (not shown) move pole- wards, the bleach mark (bars) remains a constant distance from the pole, indicating that kinetochore microtubules depolymer- ize primarily at kinetochores. Images were obtained before bleaching and at the indicated times after. The spindle is about 20 mm long. d, Photoactivation of caged fluorescein?tubulin incorporated into a Xenopus extract spindle. Images were obtained at 60-s intervals, the mark moves at a rate of 2?3 mm min ?1 , and the spindle is about 40 mm long. (Image courtesy of T. Kapoor and the MBL Cell Division Group, Marine Biol. Lab., Woods Hole, Massachusetts). e, Fluorescent speckles in a Xenopus extract spindle. Imaging of a low density of rhodamine-labelled tubulin (red) generates speckles that can be fol- lowed as fiduciary marks 59 . The left panel shows the whole spindle; DNA is shown in green. The right panel shows a series of strips from the centre of this spindle taken at 10-s intervals and displayed side by side (a kymograph). The diagonal streaks rep- resent individual speckles moving pole- wards at a rate of 2?3 mm min ?1 as a result of flux. (Image courtesy of A. Desai, P. Maddox and the MBL Cell Division Group.) � 2001 Macmillan Magazines Ltd historical perspective measuring endogenous forces and applying artificial ones. How the forces that move chromosomes are generated at a molecular level is one of the oldest questions in mitosis research. Anaphase A and B were shown to be bio- chemically distinct in their responses to poisons in the 1940s (refs 16, 17). Models from around that time show forces (Fig. 2a), but modern ideas of their molecular basis had to wait for the discovery of the mechanisms of muscle contraction and protein polymerization. Since the 1960s, two lines of thought have predominated ? force from polymerization dynamics 7 (Fig. 2b, d, e) and force from motor-protein activity 44 (Fig. 2c, f). We now know that depolymerization can generate forces on chromosomes in vitro 9,45,46 . We also know that several different kinesin family mem- bers, as well as cytoplasmic dynein, localize to spindles and kinetochores, and have key functions in spindle assembly and perhaps also chromosome movement 11,12,47 (Figs 2c, f and 4). At present, something of a gulf exists between dynamics-centered and motor-centered views of spindle assembly and force generation, although it seems inevitable that the real answer will involve integration of both views. So far neither genetics nor biochemistry has revealed a single key molecular mechanism at the heart of anaphase A or B movement. Imaging the effect on chromosome move- ment rate of removing candidate motors 12,48,49 is a good start on this prob- lem, but will not be enough. Force-produc- ing systems may be partially redundant, and the likely existence of separate force- generating and velocity-governing systems will complicate interpretation of velocity data. Full understanding of the molecular basis of force generation in mitosis will probably require direct measurement of forces as a function of genetic or biochem- ical manipulation, as well as biochemical reconstitution. Colchicine has long been known to arrest cells in mitosis 5 (Fig. 5a), but the idea that spindle damage activates a checkpoint pathway, rather than blocking progression of a series of interdependent cell-cycle events, is a recent one 50 . It took identifica- tion of the Mad and Bub proteins, which are required for mitotic arrest but not nec- essarily for normal mitosis, to make this idea concrete 51,52 . Partly because checkpoint proteins seem to be more conserved between yeast and man than other mitotic components (Fig. 5b), we may understand how the checkpoint works before we under- stand how chromosomes move 10,11 . The two known motor proteins present at kineto- chores, CenpE and dynein, seem to be involved in sensing microtubule attach- ment 53,54 , although they may also function in chromosome movement 11,49.55 . Recruitment of motors to unattached kine- tochores may facilitate microtubule cap- ture, and thus repair of spindle defects. Microtubule sensing and force generation at kinetochores must be closely interrelated, and to understand one we may have to understand the other. This is a rich chal- lenge for the future. Timothy Mitchison is in the Deparment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA Edward. D. Salmon is in the Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA e-mail: timothy_mitchison@hms.harvard.edu Nature Cell Biology gratefully acknowledges all the publishers who provided images for this work. 1. Flemming, W. Zellsubstanz, Kern und Zelltheilung (FCW Vogel, Leipzig, 1882). 2. Wilson, E.B. The Cell in Development and Heredity 3rd edn (Macmillan, New York, 1928). 3. Schrader, F. Mitosis, the Movements of Chromosomes in Cell Division 2nd edn (ed. Dunn, L. C.; Columbia Univ. Press, New York, 1953). 4. Mazia, D. in The Cell Vol. 3 (eds Brachet, J. & Mirsky, A. E.) 77?412. (Academic, New York, 1961). 5. Dustin, P. 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Figure 5 Mitotic arrest and the spindle- assembly checkpoint. a, Image of cells drawn in 1889 by Pernice 60 from a fixed preparation of dog intestine after admin- istration of a lethal dose of colchicine. This was cited by Dustin 5 as the first pub- lished observation of mitotic arrest by this tubulin-binding drug. The stain emphasizes chromatin. Note the abun- dant arrested mitotic cells. (Adapted from ref. 5.) b, Recent image of part of a PtK 2 cell arrested in mitosis with the Eg5 blocker monastrol 61 , stained for DNA (blue), kinetochores (red) and Mad2 (green). The paired kinetochores of three chromosomes can be seen. Each chromo- some has one Mad2-negative and one Mad2-positive kinetochore. Recruitment of Mad2 to kinetochores is thought to reflect activation of the spindle-assembly checkpoint that arrests the cell in mitosis 10,11 . (Image courtesy of T. Mayer and T. Kapoor, Dept Cell Biol., Harvard Med. School, Boston, Massachusetts.) � 2001 Macmillan Magazines Ltd 8. Inoue, S. 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Cell Biol. 150, 975?988 (2000). historical perspective NATURE CELL BIOLOGY VOL 3 JANUARY 2001 http://cellbio.nature.com E21 "
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