Emergent mechanics of mammalian chromosome segregation

University Of California, San Francisco, San Francisco CA

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Abstract

Project Summary/Abstract Every time a cell divides, it must accurately segregate its chromosomes for daughter cells to inherit an intact genome. The spindle and kinetochore are the large cellular machines that drive this segregation, and their failures can give rise to birth defects and cancer. In mammals, we now have a near complete list of these machines’ molecules, and know much about their biochemistry and structure. Yet, despite the spindle and kinetochore playing an essential physical role – moving chromosomes – how their molecules give rise to their emergent physical properties and function remains poorly understood. In large part, this is because of the challenges of working with large cellular machines vitro, and of probing mechanics in vivo. To meet this challenge, our lab set out to bring controlled mechanical perturbations inside dividing mammalian cells, and to combine them with precise molecular ones. Key to our efforts, we can now use microneedle manipulation to exert local, controlled forces in dividing mammalian cells. We combine physical and molecular perturbations of live cells with imaging, modeling and in vitro work to ask: How do many thousands of nm-scale molecules generating force give rise to the µm-scale spindle’s architecture, mechanics and dynamics, which together drive its function? How do thousands of kinetochore molecules work together to robustly slide on yet grip microtubules, and to monitor physical attachment signals to control attachment stability and cell cycle progression? These are the questions we seek to answer. Our recent progress towards this goal helps motivate our future work. On the spindle front, our recent work helps us understand how opposing forces are balanced and their function in the spindle, and the role of local reinforcement and isolation in maintaining global spindle structure. We now seek to define the mechanisms and functions of the spindle’s largely achiral structure given its chiral motors, of its local heterogeneous mechanics, and of its remodeling under force to both preserve and transform its structure during mitosis. On the kinetochore front, our recent work provides insight into how low friction elements help kinetochores slide on yet grip microtubules, and into the physical cues the error correction and spindle assembly checkpoint monitor for decision-making. We now seek to understand how mechanical heterogeneity of kinetochore molecules gives rise to a robust grip, and how chromosome size impacts the physical cues monitored for error correction and spindle assembly checkpoint satisfaction, and their implications. Our long-term goal is to uncover the basic physical design principles of robust and accurate mammalian chromosome segregation. We believe that working on the spindle and kinetochore together provides conceptual and technical synergy not possible by studying them separately. More broadly, we expect that our work will in the long run help us understand how ensembles of molecules give rise to the physical properties and functions of other large and complex cellular machines.