Microtubules are cellular polymers that build a variety of essential structures inside of cells where they provide a major component of a cell’s cytoskeletal network. Dynamic microtubule arrangements and rearrangements define cell shape, provide tracks for intracellular transport, and drive cell division and motility. Thus, active remodeling of the microtubule cytoskeleton is vital for cellular function. In recent years, biochemical studies of microtubules and their associated proteins have provided important insight into the molecular mechanisms underlying the dynamics of individual microtubule polymers. However, the rules governing how individual microtubules interact to give rise to dynamically-evolving cytoskeletal network architectures are still largely unknown. This project will employ a multidisciplinary approach to elucidate how microtubule-microtubule interactions encode the remodeling of the microtubule network, specifically focusing on migrating cells. The ability to reconstitute and manipulate the dynamic architecture of cytoskeletal ensembles will ultimately allow the control of cellular behavior, as well as the future development of biologically-inspired active materials. The project will provide for a diverse interdisciplinary training of undergraduate and graduate students and additional outreach efforts will be carried out in local schools and a science museum.

The goal of this research is to elucidate the role of microtubule-microtubule interactions in the dynamic remodeling of the microtubule cytoskeleton, with a particular focus on microtubule network organization in the context of cell migration. The hypothesis is that nodes of microtubule-microtubule interactions serve as focal points for network remodeling, providing encoded microdomains for localized protein activity, and endowing the network with enhanced resistance to a variety of perturbations. To test this hypothesis, this project will combine cellular studies with in vitro reconstitution approaches and computational modeling. State-of-the-art imaging will be used to determine the properties of microtubule interaction nodes, as a function of angle, protein localization and microtubule dynamics parameters in the lamella of epithelial (LLC-PK1) and migrating (B16 melanoma) cells. In vitro, microtubule interactions will be reconstituted in the presence of distinct classes of microtubule-associated-proteins (MAPs) that target and regulate microtubule end dynamics, stabilize the microtubule polymer lattice, and induce polymer damage and severing. The network topology will be controlled using micropatterning techniques; biochemical and mechanical perturbations will be exerted using microfluidics and laser severing; and ensemble behavior will be modeled using computational simulations. Predictions obtained using in silico and in vitro approaches will be directly tested by observations of microtubule interactions in cells. Together, these approaches will uncover the interplay of biochemistry, mechanics and dynamics in a physiologically-relevant context. In addition to the immediate relevance for understanding cellular processes such as cell motility and neuronal growth cone guidance, the mechanisms identified here will be broadly important in the developmental context, where cytoskeleton-driven morphological changes define multicellular tissue and organ structures through the process of differentiation.

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.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Richard Cyr
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Vanderbilt University Medical Center
United States
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