Order from Chaos: How kinetochores organize microtubules in the mitotic spindle

Abstract

Accurate chromosome segregation during mitosis relies on the precise coordination of kinetochore-attached microtubules. While individual microtubules exhibit highly variable, stochastic growth and shortening dynamics, they must cooperate within the spindle to prevent chromosome mis-segregation and aneuploidy. This dissertation investigates the biophysical mechanisms that organize this stochastic chaos into robust cellular behaviors. First, I evaluate how mechanical forces promote chromosome biorientation with a computational model of the budding yeast spindle. I show that traditional error-correction mechanisms—including catch-bond behavior, tension-sensitive kinase activity, and geometric bias—are insufficient on their own to achieve timely biorientation. However, incorporating a direction-sensitive grip that specifically destabilizes side-attached kinetochores sliding toward the pole successfully recapitulates in vivo biorientation times. Second, using a novel dual laser trap assay and data-driven stochastic modeling, I demonstrate that pairs of growing microtubules are synchronized via mechanical coupling under a shared tensile load. Finally, I outline a framework to extend our models of microtubule growth to spindles with bundled kinetochore-microtubules in growth and shortening. Together, this work reveals that direction-sensitive grip and mechanical load-sharing act as critical, self-correcting organizing influences that tame microtubule heterogeneity to ensure mitotic fidelity.