Modeling mitotic spindle assembly

University Of California At Davis, Davis CA

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Abstract

Modeling mitotic spindle assembly Mitotic spindle is a complex molecular machine segregating chromosomes before cell division. It has been of great interest for fundamental biological research for more than a century, in addition to being one of the most medically important cell structures, as its malfunction leads to birth defects, cancer and death. While molecular inventory and general principles of the spindle mechanics are becoming clear, detailed understanding of the spindle's systems biology is lacking. Our long-term goal is systems-level quantitative understanding of mitotic spindle's mechanochemistry. This understanding has to be achieved in stages, first answering simpler, and then more difficult questions, such as: How do structurally different microtubule populations interact to ensure rapid and accurate spindle assembly? How are multiple molecular motors and microtubule dynamics integrated to determine precise spindle length and spatial positioning of the spindle structures in complex-shaped cells? Do actin, myosin and membrane dynamics affect spindle development? We will answer these questions by using a novel combination of mathematical analysis, computer simulations and model-driven experiments to test the general hypothesis that actions of motor-, microtubule-, and actomyosin-generated forces combine with microtubule dynamics to rapidly and accurately assemble the spindle, determine its length, and position it in the cell. We base this hypothesis on the observations and modeling estimates suggesting that: (i) In many cells, both centrosomal and chromosomal microtubules contribute to spindle assembly;(ii) Dynein motor pulling forces, actomyosin contraction, and microtubule dynamics contribute to microtubule asters'positioning at the cell center;(iii) Kinesin, dynein and actomyosin forces and transport regulate mitotic spindle and furrow lengths in Drosophila syncytium. Based on these results, the specific aims are to: 1. Test the hypothesis that centrosomal and chromosomal microtubule dynamics are integrated and coordinated in time to achieve rapid and accurate mitotic spindle assembly. 2. Test the hypothesis that balance of three forces [unreadable]dynein pulling, actomyosin contraction, and microtubule pushing [unreadable]is responsible for positioning of microtubule asters. 3. Test the hypothesis that balance of intrinsic kinesin forces and extrinsic dynein, microtubule and actomyosin forces, and motor transport, determine lengths and positions of the mitotic spindle and furrow in Drosophila syncytium. The proposed theoretical and experimental work will result in (i) in silico reconstitution of the mitotic spindle structures, (ii) quantitative understanding how multiple polymer/motor force balance and dynamics regulate mitotic spindle assembly, size and positioning, and (iii) development of a novel modeling framework applicable to a broad variety of cell mechanical problems. An improved understanding of mitotic mechanisms will lead to more effective development of new therapies for treatment of mitosis defect-related dysfunctions such as aneuploidy associated with birth defects and cancer. The modeling framework will be applicable for a number of fundamental mechanochemical processes such as cytokinesis and cell motility, quantitative understanding of which is important for biomedical applications.