The mitotic spindle forms during cell division and separates chromosomes into the daughter cells. It is required for normal eukaryotic cell division. In most cells, the division plane position and orientation is controlled by spindle position and orientation. However, the force mechanisms underlying spindle positioning are ill-understood. Two alternative models have been proposed. One invokes microtubule interactions with the cell cortex, and the other with the cell cytoplasm. The goal is to discover which model (if not both) is correct by using modeling, simulation, and experiments in C. elegans early embryos. The project team has skills in biophysical theory, experiment, mathematical modeling, and simulation. An essential difference between the two models is whether microtubules interact actively or passively with the cytoplasm, but given the system's complexity it is difficult to discriminate with experiment alone. We will use modeling and simulation to predict cytoplasmic flows associated with each model, and their combinations, and compare these to experimental measurements of actual flows. Detailed hydrodynamic interactions have not been previously accounted for in modeling spindle dynamics, and requires novel methods for efficiently and accurately capturing spindle microtubules interacting with each other, the cytoplasmic fluid, and the cell periphery. We will compare the predicted dynamics to new experimental measurements that simultaneously capture spindle structure and dynamics, and cytoplasmic motions. Comparisons will be made between predicted and observed responses under physical, molecular, and genetic perturbations. Intellectual Merit: The proposed work will bring a new approach to modeling mitotic spindle dynamics and positioning. The integrated experimental and theoretical approach will enable new insights into the mechanisms of positioning and asymmetric cell division. The project will contribute to the broader efforts to understand the mitotic spindle and cell division, a long-standing fundamental problem in cell biology. This work will expand technical knowledge in cellular biology, biophysics, experimental technique, statistical physics, applied math, fluid dynamics, partial differential equations, and numerical analysis.

Public Health Relevance

This research will help illuminate and resolve fundamental biological issues on the role and control of the spindle and microtubules in cell division and organismal development. The project is significant for medicine and human health as the spindle and microtubules are targets for chemotherapeutic drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-CBCB-5 (BM))
Program Officer
Deatherage, James F
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New York University
Biostatistics & Other Math Sci
Schools of Arts and Sciences
New York
United States
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Redemann, Stefanie; Baumgart, Johannes; Lindow, Norbert et al. (2017) C. elegans chromosomes connect to centrosomes by anchoring into the spindle network. Nat Commun 8:15288
Blackwell, Robert; Edelmaier, Christopher; Sweezy-Schindler, Oliver et al. (2017) Physical determinants of bipolar mitotic spindle assembly and stability in fission yeast. Sci Adv 3:e1601603
Nazockdast, Ehssan; Rahimian, Abtin; Needleman, Daniel et al. (2017) Cytoplasmic flows as signatures for the mechanics of mitotic positioning. Mol Biol Cell 28:3261-3270
Wu, Hai-Yin; Nazockdast, Ehssan; Shelley, Michael J et al. (2017) Forces positioning the mitotic spindle: Theories, and now experiments. Bioessays 39:
Rincon, Sergio A; Lamson, Adam; Blackwell, Robert et al. (2017) Kinesin-5-independent mitotic spindle assembly requires the antiparallel microtubule crosslinker Ase1 in fission yeast. Nat Commun 8:15286
Blackwell, Robert; Sweezy-Schindler, Oliver; Baldwin, Christopher et al. (2016) Microscopic origins of anisotropic active stress in motor-driven nematic liquid crystals. Soft Matter 12:2676-87
Gao, Tong; Blackwell, Robert; Glaser, Matthew A et al. (2015) Multiscale modeling and simulation of microtubule-motor-protein assemblies. Phys Rev E Stat Nonlin Soft Matter Phys 92:062709
Gao, Tong; Blackwell, Robert; Glaser, Matthew A et al. (2015) Multiscale polar theory of microtubule and motor-protein assemblies. Phys Rev Lett 114:048101
Foster, Peter J; F├╝rthauer, Sebastian; Shelley, Michael J et al. (2015) Active contraction of microtubule networks. Elife 4:
Sazer, Shelley; Lynch, Michael; Needleman, Daniel (2014) Deciphering the evolutionary history of open and closed mitosis. Curr Biol 24:R1099-103

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