Modeling of chromosome motility during mitosis Melissa K Gardner and David J Odde Chromosome motility is a highly regulated and complex process that ultimately achieves proper segregation of the replicated genome. Recent modeling studies provide a computational framework for investigating how microtubule assembly dynamics, motor protein activity and mitotic spindle mechanical properties are integrated to drive chromosome motility. Among other things, these studies show that metaphase chromosome oscillations can be explained by a range of assumptions, and that non-oscillatory states can be achieved with modest changes to the model parameters. In addition, recent microscopy studies provide new insight into the nature of the coupling between force on the kinetochore and kinetochore–microtubule assembly/disassembly. Together, these studies facilitate advancement toward a unified model that quantitatively predicts chromosome motility. Addresses Department of Biomedical Engineering, University of Minnesota, 7-132 Hasselmo Hall, 312 Church Street S.E., Minneapolis, Minnesota 55455, USA Corresponding author: Odde, David J (oddex002@umn.edu) Current Opinion in Cell Biology 2006, 18:639–647 This review comes from a themed issue on Cell division, growth and death Edited by Bill Earnshaw and Yuri Lazebnik 0955-0674/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2006.10.006 Introduction During mitosis, dynamic microtubules mediate the proper segregation of the replicated genome into each of two daughter cells. These dynamic microtubules are essential components of the mitotic spindle, which is additionally composed of spindle poles, kinetochores and the replicated chromosomes themselves (reviewed in [1–3]). Microtubules have an inherent polarity, and are generally attached at their minus-end to the poles of the mitotic spindle [4,5]. Microtubule plus-ends are often associated with a kinetochore, a complex protein-based structure that serves as the essential mechanical linkage between dynamic microtubules and chromatin (reviewed in [6,7]). The structure and molecular composition of the kineto- chore is now emerging, with the finding that multiple distinct protein complexes cooperate to achieve and maintain chromosome–microtubule coupling and regu- late kinetochore-attached microtubule (kMT) plus-end assembly (reviewed in [7,8]). Microtubules are most dynamic at their plus-ends, with extended periods of polymerization (growth) and depo- lymerization (shortening) [9,10]. Changes between these two states are stochastic, characterized by ‘catastrophe’ events (a switch from the growing to the shortening state) and ‘rescue’ events (a switch from shortening to growth), a process termed dynamic instability [11]. During meta- phase, the dynamic instability of kMTs can contribute to the oscillations of chromosomes, a behavior called ‘direc- tional instability’ [12]. Although microtubule plus-ends are dynamic in a wide range of mitotic spindles, the magnitude of observed chromosome oscillations due to directional instability varies between organisms [13–18] (reviewed in [19]). In general, the dynamic instability behavior of microtubules is thought to be responsible for kinetochore attachment during prophase and prometa- phase and for the alignment of kinetochores during metaphase, such that sister chromatids are ultimately segregated into each of two nascent daughter cells during anaphase (reviewed in [20–22]). The congression of sister chromatids to a metaphase plate midway between the two spindle poles is a characteristic hallmark of metaphase, after which correction of segregation errors is relatively limited [23–25]. Therefore, prometaphase, metaphase and anaphase represent key phases in the accurate seg- regation of chromosomes. The inherent complexity of the mitotic process, or even a single phase of mitosis such as metaphase, has made it challenging to infer the underlying mechanisms of chro- mosome motility directly from experimental observation. To manage this complexity, mathematical and computa- tional models have recently been developed to integrate experimental results and provide a physical framework for further investigation of mitotic chromosome motility, in particular its control at the kinetochore. Here we review current theoretical models for kinetochore motility during mitosis. Key common elements of these theoretical mod- els for kinetochore motility include the critical role of kMT dynamic instability, and the importance of forces exerted at the kinetochore in either directly or indirectly regulating kMT dynamic instability. Other elements of spindle dynamics are considered in some of these models, depending on the specific model organism. These ele- ments include the following: microtubule poleward flux (experimental characterization in [14,26–28]); force gen- eration at the kinetochore via microtubule-associated molecular motors (reviewed in [29]); microtubule www.sciencedirect.com Current Opinion in Cell Biology 2006, 18:639–647