Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length

Abstract

Proper formation and maintenance of the mitotic spindle is required for faithful cell division. Although much work has been done to understand the roles of the key molecular components of the mitotic spindle, identifying the consequences of force perturbations in the spindle remains a challenge. We develop a computational framework accounting for the minimal force requirements of mitotic progression. To reflect early spindle formation, we model microtubule dynamics and interactions with major force-generating motors, excluding chromosome interactions that dominate later in mitosis. We directly integrate our experimental data to define and validate the model. We then use simulations to analyze individual force components over time and their relationship to spindle dynamics, making it distinct from previously published models. We show through both model predictions and biological manipulation that rather than achieving and maintaining a constant bipolar spindle length, fluctuations in pole-to-pole distance occur that coincide with microtubule binding and force generation by cortical dynein. Our model further predicts that high dynein activity is required for spindle bipolarity when kinesin-14 (HSET) activity is also high. To the best of our knowledge, our results provide novel insight into the role of cortical dynein in the regulation of spindle bipolarity.