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Vol. 16, Issue 2, 871-880, February 2005

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Cdc42 Mediates Nucleus Movement and MTOC Polarization in Swiss 3T3 Fibroblasts under Mechanical Shear Stress

Jerry S.H. Lee ^*, Melissa I. Chang ^*, Yiider Tseng ^*, and Denis Wirtz ^*   

^* Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218; Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, MD 21218; and Department of Graduate Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, MD 21218

Submitted December 19, 2003; Revised November 2, 2004; Accepted November 8, 2004
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 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, because they are both regulated by Cdc42 and dependent on microtubule structure, and physically, possibly via Hook/SUN family homologues similar to those found in Caenorhabditis elegans.

Abbreviations used: MTOC, microtubule organizing center; NR, nuclear rotation; MT, microtubule.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Corresponding author. E-mail address: wirtz{at}jhu.edu.

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