Christopher J. Edelmaier, Adam R. Lamson, Zachary R. Gergely, Saad Ansari, Robert Blackwell, J. Richard McIntosh, Matthew A. Glaser, Meredith D. Betterton (2019). Biorxiv DOI: 10.1101/649913
The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes in mitosis and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Starting from an initial condition that mimics the onset of mitosis, the model assembles a bipolar spindle, attaches to and aligns chromosomes, corrects attachment errors, and segregates the chromosomes to the poles. The model exhibits quantitative agreement with data from fission yeast. By examining model requirements for long-lived biorientation, we find that progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence are important for robust chromosome alignment. Spindle length changes consistent with the force-balance model, and large fluctuations in spindle length can occur when the kinetochore-microtubule attachment life-time is long. During spindle assembly, the primary spindle force generators are kinesin-5 motors and crosslinkers, while interkinetochore stretch becomes important after biorientation occurs. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.