THE NUCLEUS IN CELL POLARIZATION, MIGRATION, AND MECHANOTRANSDUCTION Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Graham, David
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Many signaling pathways converge on the nucleus to regulate critical nuclear events such as transcription, DNA replication and cell cycle progression. While the vast majority of research in this area has focused on signals generated in response to hormones or other soluble factors, the nucleus also responds to mechanical forces. During the past decade or so, much has been learned about how mechanical force can affect transcription, as well as the growth and differentiation of cells. Much has also been learned about how force is transmitted via the cytoskeleton to the nucleus and then across the nuclear envelope to the nuclear lamina and chromatin. The nucleus has long been postulated to play a critical physical role during cell polarization and migration, however, that role has not been defined or rigorously tested. Here, I enucleated cells to test the physical requirement of the nucleus during polarization and directed migration. Using enucleated mammalian fibroblasts (cytoplasts), I found that polarity establishment and cell migration in 1D and 2D occur without the nucleus. Cytoplasts migrate toward soluble (chemotaxis) and surface-bound (haptotaxis) extracellular cues and migrate collectively in scratch-wound assays. Consistent with previous studies, migration in 3D environments was dependent upon the nucleus. In part, this may reflect the decreased force exerted by cytoplasts on mechanically compliant substrates. This response is mimicked in both cells with nuclear lamina defects, and upon inhibition of actomyosin-based contractility. Together, my observations reveal that the nucleus is dispensable for polarization and migration in 1 and 2D, but critical for ¬proper cell mechanical responses.
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DOI
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Advisor
  • Hoffman, Brenton
  • Rubin, Janet
  • Burridge, Keith
  • Bear, James
  • Jacobson, Ken
  • Cheney, Richard
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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