Collaborative research: MODULUS: Nuclear envelope shape change coordination with chromosome segregation in mitosis in fission yeast

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For over 100 years, biologists have worked to make sense of how cells move chromosomes to the correct locations for successful cell division in a process known as mitosis. Because mitosis depends on dozens of protein types, it is challenging to predict how mitosis works. Therefore, this project is building a mathematical model of mitosis. An analogy for mitosis is that the cell first builds a crane (the mitotic spindle) and then uses it to move large objects (the chromosomes) to their correct places (chromosome segregation). Starting with the details of a subset of the key molecules, including the chromosomes and the mitotic spindle, new algorithms are simulating mitosis as a whole. The model is developed hand-in-hand with experiments in fission yeast. This project is going beyond previous work to address closed mitosis, in which the nuclear envelope remains intact, and chromosome segregation and nuclear division occur together. To understand closed mitosis as a whole, this project is identifying the mechanisms by which the spindle affects the envelope and the envelope affects the spindle for successful mitosis. Building this more realistic model of simultaneous nuclear division and chromosome segregation in mitosis will ultimately allow study of mitosis across life, particularly in nuclear envelope function (closed, semi-open, and open mitosis). Understanding how cells divide is important in the long run for helping correct errors in cell division. The project is developing interdisciplinary education in biophysics, cellular biology, and mathematical biology. The project is extending an international, online biophysics seminar that makes research results broadly available outside elite institutions and at no cost, broadening participation in biophysics.This project is modeling closed mitosis by bringing together membrane and cytoskeletal modeling tools, which are challenging to integrate and implement with tractable algorithms. The first objective is extending a model of mitosis to include a deformable elastic nuclear envelope, to integrate the spindle and chromosomes with boundary-integral and triangulated-membrane models of the nuclear envelope. The second objective is to identify how nuclear envelope forces and deformation drive successful chromosome segregation in closed mitosis, by modeling and measuring envelope shape, spindle dynamics, and chromosome movement in cells with perturbations to the nuclear envelope. The project is developing new algorithms and software for simulation of membrane-cytoskeleton interactions, which are difficult to model currently.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.