Insights into cytoskeletal behavior from computational modeling of dynamic microtubules in a cell-like environment

Interdisciplinary Center for the Study of Biocomplexity, University of Notre Dame, Notre Dame, IN 46556 USA.
Journal of Cell Science (Impact Factor: 5.43). 12/2006; 119(Pt 22):4781-8. DOI: 10.1242/jcs.03240
Source: PubMed


Microtubule dynamic instability plays a fundamental role in cell biology, enabling microtubules to find and interact with randomly distributed cargo and spatially localized signals. In vitro, microtubules transition between growth and shrinkage symmetrically, consistent with the theoretical understanding of the mechanism of dynamic instability. In vivo, however, microtubules commonly exhibit asymmetric dynamic instability, growing persistently in the cell interior and experiencing catastrophe near the cell edge. What is the origin of this behavior difference? One answer is that the cell edge causes the asymmetry by inducing catastrophe in persistently growing microtubules. However, the origin of the persistent growth itself is unclear. Using a simplified coarse-grained stochastic simulation of a system of dynamic microtubules, we provide evidence that persistent growth is a predictable property of a system of nucleated, dynamic, microtubules containing sufficient tubulin in a confined space--MAP activity is not required. Persistent growth occurs because cell-edge-induced catastrophe increases the concentration of free tubulin at steady-state. Our simulations indicate that other aspects of MT dynamics thought to require temporal or spatial changes in MAP activity are also predictable, perhaps unavoidable, outcomes of the "systems nature" of the cellular microtubule cytoskeleton. These include the mitotic increase in microtubule dynamics and the observation that defects in nucleation cause changes in the behavior of microtubule plus ends. These predictions are directly relevant to understanding of the microtubule cytoskeleton, but they are also attractive from an evolutionary standpoint because they provide evidence that apparently complex cellular behaviors can originate from simple interactions without a requirement for intricate regulatory machinery.

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    • "Recent theoretical work has focused on determining how much of the dynamic instability process in cells can be attributed to cellular context before consideration of MAP activities. Several studies have made the case that persistent microtubule growth properties observed in some cell types, and related aspects of the dynamics measurements, can be explained by the relationship of the cell boundary to the average length of microtubule polymers in the system (Gregoretti et al., 2006; Vorobjev and Maly, 2008). Assuming that growing microtubules switch to shortening at the cell cortex, it was shown that a system making lots of otherwise long microtubules builds up free subunits from the induced catastrophes at the cell boundary. "
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    ABSTRACT: Microtubule polymers typically function through their collective organization into a patterned array. The formation of the pattern, whether it is a relatively simple astral array or a highly complex mitotic spindle, relies on controlled microtubule nucleation and the basal dynamics parameters governing polymer growth and shortening. We have investigated the interaction between the microtubule nucleation and dynamics parameters, using macroscopic Monte Carlo simulations, to determine how these parameters contribute to the underlying microtubule array morphology (i.e. polymer density and length distribution). In addition to the well-characterized steady state achieved between free tubulin subunits and microtubule polymer, we propose that microtubule nucleation and extinction constitute a second, interdependent steady state process. Our simulation studies show that the magnitude of both nucleation and extinction additively impacts the final steady state free subunit concentration. We systematically varied individual microtubule dynamics parameters to survey the effects on array morphology and find specific sensitivity to perturbations of catastrophe frequency. Altering the cellular context for the microtubule array, we find that nucleation template number plays a defining role in shaping the microtubule length distribution and polymer density.
    Full-text · Article · Oct 2011 · Computational biology and chemistry
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    • "Stochastic discrete models of biopolymer dynamics have been investigated in [4] [5] [16] [17] [18] [12] [13] [19], among others. Here we present a stochastic model that represents the same set of reactions as our continuous model in [14], except for the nucleation of fresh microtubules which is an unnecessary complication for the case studied here. "
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    ABSTRACT: We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady state microtubules assembled from MAP-free tubulin. Both experimentally and theoretically we study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. We find that to be an effective suppressor of microtubule dynamics a drug must primarily suppress the loss of GDP tubulin from the microtubule tip.
    Full-text · Article · Aug 2011 · Physical Biology
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    • "A second factor possibly regulating dimer/polymer partitioning is the rate of MT nucleation from centrosomes. Several computational models have suggested that MT nucleation rate could have a significant impact on tubulin partitioning within a cell (Mitchison and Kirschner, 1987; Gregoretti et al., 2006), although this has not been tested experimentally. Additional mechanisms that could contribute to tubulin partitioning between dimer and polymer pools include regulation of the total tubulin level or sequestration of tubulin dimers to render them unable to polymerize (Mitchison and Kirschner, 1987; Holmfeldt et al., 2007; Sellin et al., 2008). "
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    ABSTRACT: Stathmin is a microtubule-destabilizing protein ubiquitously expressed in vertebrates and highly expressed in many cancers. In several cell types, stathmin regulates the partitioning of tubulin between unassembled and polymer forms, but the mechanism responsible for partitioning has not been determined. We examined stathmin function in two cell systems: mouse embryonic fibroblasts (MEFs) isolated from embryos +/+, +/-, and -/- for the stathmin gene and porcine kidney epithelial (LLCPK) cells expressing stathmin-cyan fluorescent protein (CFP) or injected with stathmin protein. In MEFs, the relative amount of stathmin corresponded to genotype, where cells heterozygous for stathmin expressed half as much stathmin mRNA and protein as wild-type cells. Reduction or loss of stathmin resulted in increased microtubule polymer but little change to microtubule dynamics at the cell periphery. Increased stathmin level in LLCPK cells, sufficient to reduce microtubule density, but allowing microtubules to remain at the cell periphery, also did not have a major impact on microtubule dynamics. In contrast, stathmin level had a significant effect on microtubule nucleation rate from centrosomes, where lower stathmin levels increased nucleation and higher stathmin levels reduced nucleation. The stathmin-dependent regulation of nucleation is only active in interphase; overexpression of stathmin-CFP did not impact metaphase microtubule nucleation rate in LLCPK cells and the number of astral microtubules was similar in stathmin +/+ and -/- MEFs. These data support a model in which stathmin functions in interphase to control the partitioning of tubulins between dimer and polymer pools by setting the number of microtubules per cell.
    Full-text · Article · Jul 2009 · Molecular biology of the cell
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