A Mechanomolecular Model for Chromosome Movement During Mitosis

Abstract

During mitosis chromosomes attach to dynamic microtubules in order to move to the cell equator. Kinetochores facilitate chromosome movement by maintaining a floating grip on inserted polymerizing or depolymerizing microtubules. In many vertebrates, chromosomes experience striking oscillatory movement both close to a pole and around the equator. Several chemical species that affect microtubule dynamics as well as proteins that bind to the microtubule lattice have been localized at kinetochores. Yet, there is no clear understanding of the force producing mechanism at microtubule attachment sites, and of how movement is controlled and coordinated at kinetochores so that a chromosome pinpoints the cell equator. Here we develop a mathematical model of chromosome motility that addresses the above two questions. First, we consider force production at kinetochores by developing a molecular motor model that describes molecular scale interactions between several kinetochore binders and an inserted microtubule. We find that for weak binding and low activation energies, the motor produces velocities that are fairly insensitive to loads and depend on the inserted polymer growth/shortening rates, in agreement with chromosome movement data. Then, we incorporate the molecular motor into a chromosome movement model in which motility results due to feedback between mechanical loads that arise from spindle-chromosome interactions and kinetochore chemical reactions that involve a force sensing kinase and a microtubule depolymerase.Numerical simulations show that kinetochore chemical control of movement is a robust mechanism for chromosome oscillations and centering at the equator. Further, we observe that proper transition between mitotic stages is strongly influenced by kinetochore reactions, which indicates that motility does not solely result from “tug of war” between opposing forces. We find that our proposed mechanism is sufficient to recreate chromosome movement from prometaphase to anaphase, in good agreement with experimental data.