A Quantitative Force Map of the Mitotic Spindle

The goal of this research proposal is to understand the way in which cells engineer micrometerscale structures. In particular, we aim to understand how different force generating systems collectively define the shape of the metaphase spindle. The bipolar structure of the spindle is inherently linked to its function, which is to precisely partition the genetic material onto two daughter cells. The shape of the metaphase spindle arises through the integrated action of molecular and physical mechanisms that generate and respond to force. Despite its importance for cell proliferation and procreation, we currently cannot explain how this dynamic structure generates and responds to forces while maintaining overall stability. To gain perspective on how the spindle integrates physical forces, it is essential to determine its mechanical properties. Here, we propose to gain insights into the micro-mechanical properties of the metaphase spindle by analyzing deformations that arise in the structure in response to applied forces. To understand how different force generating systems collectively define the shape of the metaphase spindle, we will use a combination of contact-free rheology, in vitro reconstitution and biochemical perturbation assays, mechanical and biophysical measurements, and active liquid crystal theory based on general principles of non-equilibrium statistical mechanics to derive a systematic force map of the metaphase spindle, which links molecular force generators to large-scale properties of the metaphase spindle.