Modelling collective mechanics of microtubule aster motility and positioning by molecular motors

Abstract

Microtubules (MTs) and MT associated proteins form an essential component of the eukaryotic cytoskeleton. Asters are radial arrays of MTs, involved in vital cellular processes such as spindle assembly,chromosome segregation, intracellular transport, cell motility and organelle positioning. While several studies have addressed mechanisms for movement and positioning of a single or a pair of asters, only a few studies report the mechanical basis of multi aster positioning. Understanding how their numbers and position is mechanically regulated is the focus of this study. Using computational models, I have studied the mechanical basis of multiple-asters in confinement. In order to determine the general principles of multi-aster behaviour, the MT-motor parameter space was extensively explored and the key findings are discussed in the thesis. The multi-aster centering in meiotic oocytes of mouse was recapitulated in a minimal model of dynein gradient, coupling dyneins, MT dynamics and cortical pushing. This suggests motor gradient as a mechanism for directed motility of small asters in large cells. While segregated arrangement of asters emerged with a hexagonal dominance, in presence of kinesin-5 motors and stabilized MTs at optimal system size. A similar hexagon ordering observed in ascidian meiotic oocytes, validated the simulation results. On cortical localization of dyneins, dynamic asters self-organized into collective rotational motion. This suggests possible mechanisms that may have evolved to suppress such motions in vivo. To explicitly simulate cortical dyneins, yeast dynein was modeled and the motor number dependent MT transport statistics was comparable to the MT gliding experiments. The combined a↵ect of MTs, motors and system size on mult-aster motility and position is demonstrated. This study provides a framework for theoretical understanding of the principles of multi-aster mechanics in spindle assembly, sub-cellular organization and embryogenesis