Apr. 24 (Thursday) Alex Mogilner (UC Davis)
Reverse engineering of mitotic spindle
Abstract:
Mitotic spindle is a complex mechanochemical machine segregating spindle poles and chromosomes in a carefully orchestrated way. For example, during Drosophila embryonic development, the distances between spindle poles and chromosomes intermittently increase linearly and stagnate in a well-defined and reproducible fashion. While a number of molecular perturbations have revealed the basic mechanisms of multiple motor and microtubule actions underlying spindle dynamics, a complete picture of how motor and microtubule forces are integrated is still lacking.
We undertook systemic analysis to identify potential mechanisms of force integration that will reproduce spindle development in Drosophila embryo. First, computer assembled millions of different models based on various possible combinations of molecular motors' mechanics and kinetics. Then, searches in the 'model space' based on repeated stochastic optimization using genetic algorithms followed by cluster analysis identified distinct strategies for force integration. We discovered that increasing the amount of quantitative experimental data, used to estimate how adequate the models are, lead to a decrease in the total number of distinct resulting successful strategies. Our searches identified but a few distinct strategies that can reproduce pole separation in both wild type and mutant or biochemically inhibited embryos. In addition to identifying the unique way in which the motors and microtubules are regulated to achieve rapid, robust and accurate mitosis in Drosophila, the optimization process uncovered novel mechanical properties of the participating molecular motors. Finally, analysis of different force balance strategies revealed general design principles that are common among all plausible models.