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A more recent version of this article appeared on February 1, 2005
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Submitted on December 19, 2003
Revised on November 2, 2004
Accepted on November 8, 2004
Departments of *Chemical and Biomolecular Engineering and Materials Science and Engineering and Graduate Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, MD 21218
Monitoring Editor: Jennifer Lippincott-Schwartz
Nucleus movement is essential during nucleus positioning for tissue growth and development in eukaryotic cells. However, molecular regulators of nucleus movement in interphase fibroblasts have yet to be identified. Here, we report that nuclei of Swiss 3T3 fibroblasts undergo enhanced movement when subjected to shear flows. Such movement includes both rotation and translocation and is dependent on microtubule, not F-actin, structure. Through inactivation of Rho GTPases, well-known mediators of cytoskeleton reorganization, we demonstrate that Cdc42, not RhoA or Rac1, controls the extent of nucleus translocation, and more importantly, of nucleus rotation in the cytoplasm. In addition to generating nuclei movement, we find that shear flows also causes repositioning of the nearby MTOC in the direction of flow. This behavior is also controlled by Cdc42 via the Par6/protein kinase C
pathway. These results are the first to establish Cdc42 as a molecular regulator of not only shear-induced MTOC polarization in Swiss 3T3 fibroblasts, but also of shear-induced microtubule-dependent nucleus movement. We propose that the movements of MTOC and nucleus are coupled chemically, as they are both regulated by Cdc42 and dependent upon microtubule structure, and physically, possibly via Hook/SUN family homologues similar to those found in C. elegans.
Corresponding author.
E-mail: wirtz{at}jhu.edu
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