model for the regulatory network controlling the dynamics of kinetochore microtubule plus-ends and poleward flux in metaphase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 19; pp. 7846 - 7851
• Main Authors: Fernandez, Nicolas, Chang, Qiang, Buster, Daniel W, Sharp, David J, Ma, Ao
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.05.2009; National Acad Sciences
• Subjects: Algorithms; Animals; Biological Sciences; Cell division; Cell lines; Chromosomes; Computer Simulation; Data processing; Depolymerization; Drosophila; Drosophila Proteins - metabolism; Kinesin - metabolism; Kinetochores; Kinetochores - metabolism; Metaphase; Microtubule-Associated Proteins - metabolism; Microtubules; Microtubules - metabolism; Mitosis; Mitotic spindle apparatus; Modeling; Models, Biological; Models, Statistical; Monte Carlo simulation; Polymerization; Proteins; regulatory proteins; RNA Interference; Spindle Apparatus - metabolism; Spindles; Tubulin
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0813228106

Tight regulation of kinetochore microtubule dynamics is required to generate the appropriate position and movement of chromosomes on the mitotic spindle. A widely studied but mysterious aspect of this regulation occurs during metaphase when polymerization of kinetochore microtubule plus-ends is balanced by depolymerization at their minus-ends. Thus, kinetochore microtubules maintain a constant net length, allowing chromosomes to persist at the spindle equator, but consist of tubulin subunits that continually flux toward spindle poles. Here, we construct a feasible network of regulatory proteins for controlling kinetochore microtubule plus-end dynamics, which was combined with a Monte Carlo algorithm to simulate metaphase tubulin flux. We also test the network model by combining it with a force-balancing model explicitly taking force generators into account. Our data reveal how relatively simple interrelationships among proteins that stimulate microtubule plus-end polymerization, depolymerization, and dynamicity can induce robust flux while accurately predicting apparently contradictory results of knockdown experiments. The model also provides a simple and robust physical mechanism through which the regulatory networks at kinetochore microtubule plus- and minus-ends could communicate.