Modeling of chromosome motility during mitosis

Department of Biomedical Engineering, University of Minnesota, 7-132 Hasselmo Hall, 312 Church Street S.E., Minneapolis, Minnesota 55455, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 01/2007; 18(6):639-47. DOI: 10.1016/
Source: PubMed


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.

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    • "Like chromosome congression to the metaphase plate, maintenance of alignment is believed to depend primarily on KT-associated motors (e.g., dynein, CENP-E), chromosome-associated motors (chromokinesins ), biophysical properties of the KT–MT interface (e.g., compliance of Ndc-80 molecules), and regulators of MT dynamics (e.g., kinesin 13 and Aurora B kinase). Alignment at the spindle equator can be maintained when the forces that act on the chromosomes achieve a balance (Gardner and Odde, 2006; Vladimirou et al., 2011). However, despite maintenance of overall alignment at the metaphase plate, chromosomes are not necessarily static and the plus ends of KT-bound MTs (kMTs), and thus KT–MT attachments, remain dynamic during meta- phase. "
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    ABSTRACT: Duplicated mitotic chromosomes aligned at the metaphase plate maintain dynamic attachments to spindle microtubules via their kinetochores, and multiple motor and nonmotor proteins cooperate to regulate their behavior. Depending on the system, sister chromatids may display either of two distinct behaviors, namely (1) the presence or (2) the absence of oscillations about the metaphase plate. Significantly, in PtK1 cells, in which chromosome behavior appears to be dependent on the position along the metaphase plate, both types of behavior are observed within the same spindle, but how and why these distinct behaviors are manifested is unclear. Here, we developed a new quantitative model to describe metaphase chromosome dynamics via kinetochore-microtubule interactions mediated by nonmotor viscoelastic linkages. Our model reproduces all the key features of metaphase sister kinetochore dynamics in PtK1 cells and suggests that differences in the distribution of polar ejection forces at the periphery and in the middle of PtK1 cell spindles underlie the observed dichotomy of chromosome behavior.
    The Journal of Cell Biology 05/2013; 201(4):577-93. DOI:10.1083/jcb.201301022 · 9.83 Impact Factor
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    • "Kinetochores generally bind to bundles of many MTs (up to 25–30 bundled MTs in mammalian cells), which contain both polymerizing and depolymerizing MT plus ends (McIntosh et al., 2008). Therefore, the dynamics of these kinetochore-bound MT plus ends must be, at least, partially synchronized for oscillation to occur (Civelekoglu- Scholey et al., 2006; Gardner and Odde, 2006). This is probably achieved by a much slower tubulin turnover rate (Hyman and Mitchison, 1990; Zhai et al., 1995), which could also facilitate the attachments. "
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    ABSTRACT: During mitosis, duplicated sister chromatids are properly aligned at the metaphase plate of the mitotic spindle before being segregated into two daughter cells. This requires a complex process to ensure proper interactions between chromosomes and spindle microtubules. The kinetochore, the proteinaceous complex assembled at the centromere region on each chromosome, serves as the microtubule attachment site and powers chromosome movement in mitosis. Numerous proteins/protein complexes have been implicated in the connection between kinetochores and dynamic microtubules. Recent studies have advanced our understanding on the nature of the interface between kinetochores and microtubule plus ends in promoting and maintaining their stable attachment. These efforts have demonstrated the importance of this process to ensure accurate chromosome segregation, an issue which has great significance for understanding and controlling abnormal chromosome segregation (aneuploidy) in human genetic diseases and in cancer progression.
    International review of cell and molecular biology 02/2013; 303:237-62. DOI:10.1016/B978-0-12-407697-6.00006-4 · 3.42 Impact Factor
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    • "For mammalian systems the model of Joglekar and Hunt 2002—from here on called J&H—best reflects our current understanding of how kinetochores work (Gardner and Odde 2006). The heart of the model is a simple force–balance equation between the forces exerted on kinetochores by attached microtubules and the PEFs acting on the chromosome arms (Fig. 2a). "
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    ABSTRACT: As a mechanical system, the kinetochore can be viewed as a set of interacting springs, clutches and motors; the problem of kinetochore mechanism is now one of understanding how these functional modules assemble, disassemble and interact with one another to give rise to the emergent properties of the system. The sheer complexity of the kinetochore system points to a future requirement for data-driven mathematical modelling and statistical analysis based on quantitative empirical measurement of sister kinetochore trajectories. Here, we review existing models of chromosome motion in the context of recent advances in our understanding of kinetochore molecular biology.
    Chromosome Research 02/2011; 19(3):409-21. DOI:10.1007/s10577-011-9191-x · 2.48 Impact Factor
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