Modeling of chromosome motility during mitosis

ArticleinCurrent Opinion in Cell Biology 18(6):639-47 · January 2007with5 Reads
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.
    • "(iii) Force inference and identification of mechanistic signatures, thereby revealing previously inaccessible mechanistic information. Our methodology complements forward simulation analyses (reviewed in [33, 34, 47] ) where models of kinetochore dynamics are developed from knowledge and assumptions pertaining to the biological processes and are demonstrated to qualitatively or semi-quantitatively reproduce observed behaviour under suitable parameter values. However, our analysis of 2 second resolution 3D live-cell tracking data has revealed new depths of complexity in kinetochore dynamics and choreography, substantially adding to the qualitative and quantitative constraints that these models must satisfy, including trail sister initiated switching, a bias towards lead sister initiated switching, and spatial parameter trends. "
    [Show abstract] [Hide abstract] ABSTRACT: Kinetochores are multi-protein complexes that mediate the physical coupling of sister chromatids to spindle microtubule bundles (called kinetochore (K)-fibres) from respective poles. These kinetochore-attached K-fibres generate pushing and pulling forces, which combine with polar ejection forces (PEF) and elastic inter-sister chromatin to govern chromosome movements. Classic experiments in meiotic cells using calibrated micro-needles measured an approximate stall force for a chromosome, but methods that allow the systematic determination of forces acting on a kinetochore in living cells are lacking. Here we report the development of mathematical models that can be fitted (reverse engineered) to high-resolution kinetochore tracking data, thereby estimating the model parameters and allowing us to indirectly compute the (relative) force components (K-fibre, spring force and PEF) acting on individual sister kinetochores in vivo. We applied our methodology to thousands of human kinetochore pair trajectories and report distinct signatures in temporal force profiles during directional switches. We found the K-fibre force to be the dominant force throughout oscillations, and the centromeric spring the smallest although it has the strongest directional switching signature. There is also structure throughout the metaphase plate, with a steeper PEF potential well towards the periphery and a concomitant reduction in plate thickness and oscillation amplitude. This data driven reverse engineering approach is sufficiently flexible to allow fitting of more complex mechanistic models; mathematical models of kinetochore dynamics can therefore be thoroughly tested on experimental data for the first time. Future work will now be able to map out how individual proteins contribute to kinetochore-based force generation and sensing.
    Full-text · Article · Nov 2015
    • "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 metaphase . "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · May 2013
    • "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 (CivelekogluScholey 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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Feb 2013
Show more