Modeling Reveals Cortical Dynein Regulation of Spindle Bipolarity

Abstract

Proper formation and maintenance of the mitotic spindle is required for faithful cell division. While 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. Together, our results provide novel insight into the role of cortical dynein in the regulation of spindle bipolarity. SIGNIFICANCEThe mitotic spindle is a biophysical machine that is required for cell division. Here we have paired a modeling approach with experimental data to understand the maintenance and dynamics of a bipolar mitotic spindle in the absence of chromosome interactions. We present novel roles of cortical dynein in mitosis, and demonstrate its requirement for both dynamic changes in spindle length and in antagonizing HSET in bipolar spindle formation. Model outputs predict that cortical dynein activity would be limiting in contexts where HSET activity is high and may be of therapeutic relevance in cancer contexts where HSET is often over expressed.