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Nuclear Lamin A/C Deficiency Induces Defects in Cell Mechanics, Polarization, and Migration

Jerry S. H. Lee ^*, Christopher M. Hale ^*, Porntula Panorchan ^*, Shyam B. Khatau ^*, Jerry P. George ^*, Yiider Tseng ^¶, Colin L. Stewart , Didier Hodzic  and Denis Wirtz ^* 

^* Department of Chemical and Biomolecular Engineering, and Institute for NanoBioTechnology and Howard Hughes Medical Institute graduate training program, Johns Hopkins University, Baltimore, Maryland; Cancer and Developmental Biology, National Cancer Institute, Frederick, Maryland; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; and ^¶ Department of Chemical Engineering, University of Florida, Gainesville, Florida

Correspondence: Address reprint requests to Didier Hodzic, Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel: 314-362-1082; or to Denis Wirtz, Dept. of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218. Tel: 410-516-7006; Fax: 410-516-5510.

Lamin A/C is a major constituent of the nuclear lamina, a thin filamentous protein layer that lies beneath the nuclear envelope. Here we show that lamin A/C deficiency in mouse embryonic fibroblasts (Lmna^–/– MEFs) diminishes the ability of these cells to polarize at the edge of a wound and significantly reduces cell migration speed into the wound. Moreover, lamin A/C deficiency induces significant separation of the microtubule organizing center (MTOC) from the nuclear envelope. Investigations using ballistic intracellular nanorheology reveal that lamin A/C deficiency also dramatically affects the micromechanical properties of the cytoplasm. Both the elasticity (stretchiness) and the viscosity (propensity of a material to flow) of the cytoplasm in Lmna^–/– MEFs are significantly reduced. Disassembly of either the actin filament or microtubule networks in Lmna^+/+ MEFs results in decrease of cytoplasmic elasticity and viscosity down to levels found in Lmna^–/– MEFs. Together these results show that both the mechanical properties of the cytoskeleton and cytoskeleton-based processes, including cell motility, coupled MTOC and nucleus dynamics, and cell polarization, depend critically on the integrity of the nuclear lamina, which suggest the existence of a functional mechanical connection between the nucleus and the cytoskeleton. These results also suggest that cell polarization during cell migration requires tight mechanical coupling between MTOC and nucleus, which is mediated by lamin A/C.

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