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70380048.Pdf Washington University School of Medicine Digital Commons@Becker Open Access Publications 2012 The distinct roles of the nucleus and nucleus- cytoskeleton connections in three-dimensional cell migration Shyam B. Khatau Johns Hopkins University Ryan J. Bloom Johns Hopkins University Saumendra Bajpai Johns Hopkins University David Razafsky Washington University School of Medicine in St. Louis Shu Zhang Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: http://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Khatau, Shyam B.; Bloom, Ryan J.; Bajpai, Saumendra; Razafsky, David; Zhang, Shu; Giri, Anjil; Wu, Pei-Hsun; Marchand, Jorge; Celedon, Alfredo; Hale, Christopher M.; Sun, Sean X.; Hodzic, Didier; and Wirtz, Denis, ,"The distinct roles of the nucleus and nucleus-cytoskeleton connections in three-dimensional cell migration." Scientific Reports.2,. Article number: 488. (2012). http://digitalcommons.wustl.edu/open_access_pubs/1345 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Shyam B. Khatau, Ryan J. Bloom, Saumendra Bajpai, David Razafsky, Shu Zhang, Anjil Giri, Pei-Hsun Wu, Jorge Marchand, Alfredo Celedon, Christopher M. Hale, Sean X. Sun, Didier Hodzic, and Denis Wirtz This open access publication is available at Digital Commons@Becker: http://digitalcommons.wustl.edu/open_access_pubs/1345 The distinct roles of the nucleus and nucleus-cytoskeleton connections in SUBJECT AREAS: BIOPHYSICS three-dimensional cell migration COMPUTATIONAL BIOLOGY Shyam B. Khatau1,2*, Ryan J. Bloom1*#, Saumendra Bajpai1,21, David Razafsky3, Shu Zang3, Anjil Giri1,2, CELL ADHESION Pei-Hsun Wu1,2, Jorge Marchand1,2, Alfredo Celedon2,4,5, Christopher M. Hale1,2, Sean X. Sun1,2,4, CELL SIGNALLING Didier Hodzic3 & Denis Wirtz1,2 Received 1Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA, 2Johns 27 March 2012 Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA, 3Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110, USA, 4Department of Mechanical Engineering, Accepted 5 30 May 2012 The Johns Hopkins University, Baltimore, Maryland 21218, USA, Department of Mechanical Engineering, Pontificia Universidad Cato´lica de Chile, P.O. Box 306, Santiago, 6904411, Chile. Published 3 July 2012 Cells often migrate in vivo in an extracellular matrix that is intrinsically three-dimensional (3D) and the role of actin filament architecture in 3D cell migration is less well understood. Here we show that, while recently identified linkers of nucleoskeleton to cytoskeleton (LINC) complexes play a minimal role in conventional Correspondence and 2D migration, they play a critical role in regulating the organization of a subset of actin filament bundles – requests for materials the perinuclear actin cap - connected to the nucleus through Nesprin2giant and Nesprin3 in cells in 3D should be addressed to collagen I matrix. Actin cap fibers prolong the nucleus and mediate the formation of pseudopodial D.W. ([email protected]) protrusions, which drive matrix traction and 3D cell migration. Disruption of LINC complexes disorganizes the actin cap, which impairs 3D cell migration. A simple mechanical model explains why LINC complexes and the perinuclear actin cap are essential in 3D migration by providing mechanical support to the * These authors formation of pseudopodial protrusions. contributed equally to this work. he roles of actin filament dynamics and network organization in conventional cell migration and morpho- logy on flat substrates have been studied extensively1,2. However, fibroblasts often migrate in vivo in an # Current address: extracellular matrix that is intrinsically three-dimensional (3D) and the role of actin filament architecture in T 3–5 Department of 3D cell migration is less well-understood . In particular, whether recently discovered connections between 6 Bioengineering, nucleus and cytoskeleton mediated by Linkers of the Nucleoskeleton to the Cytoskeleton (LINC) complexes play any role in cell shape, cell migration, and associated protrusion activity in 3D extracellular matrices is unknown7. Stanford University, This question is important since protrusion activity plays a central role in 3D migration8,9, as pseudopodial Stanford, California, protrusion processes allow cells to probe the pericellular matrix, locally attach to and pull on surrounding fibers, USA. and detach from them dynamically10. Corresponding local remodelling of the 3D matrix, which does not occur in 1Current address: conventional 2D migration, is required for effective cell migration inside a 3D matrix11. This question is also Department of important because cells on planar substrates display a flattened fan-like morphology, while cells completely Biomedical embedded in a more physiological 3D matrix environment often adopt a spindle-like morphology well suited 11–15 Engineering, Cornell to negotiate tight matrices . University, Ithaca, LINC complexes are protein assemblies that span the nuclear envelope and mediate physical connections 6 New York, USA. between the nuclear lamina and the cytoskeleton . These connections are mediated by interactions between SUN (Sad1/UNC-84) domain–containing proteins and KASH (Klarsicht/ANC-1/Syne-1 homology) domain–con- taining proteins at the outer nuclear membrane16–21. The down-regulation of both Sun1 and Sun2 prevents the localization of Nesprin-2 giant at the nuclear envelope6,22. The expression of either the recombinant SUN domain of Sun1 and Sun2 within the ER lumen or the KASH domain of Nesprins (nuclear envelope spectrins; also Syne) 1, 2, and 3 results in the displacement of all Nesprins from the NE to the ER6,22,23. The KASH domain of Nesprins 1, 2, and 3 can interact promiscuously with either Sun1 or Sun223. Whether Nesprins and interactions between Nesprins and Sun proteins play a role in 3D cell migration are unknown. Here we use quantitative functional live-cell assays to show that LINC complexes play a critical role in regulating 3D actin architecture in cells in 3D matrix, and mediate protrusion dynamics, which in turn drive SCIENTIFIC REPORTS | 2 : 488 | DOI: 10.1038/srep00488 1 www.nature.com/scientificreports 3D matrix remodeling and 3D cell migration. We first show how elongated shape 85% of the time (Figs. 1L and 2C). Accordingly, the lamin A/C deficiency, which disrupts LINC complexes at the nuclear global reduction of pseudopodial activity in Lmna2/2 cells faithfully envelope24,25, induces a migration phenotype only in 3D collagen reflected the small fraction of time that these cells spent in the matrices, not on conventional 2D substrates. To establish the elongated morphology (compare results in Fig 2C to Fig. 2D). molecular mechanism underlying this 3D matrix-specific defect, Similar differential protrusion activity was observed for the pair of we examined the role of LINC complexes and found that LINC control (scrambled shRNA) and shRNA lamin A/C-depleted C2C12 complex molecules Nesprin 2 giant and Nesprin 3 differentially cells (Fig. 1M). Moreover, the speed of Lmna2/2 cells in the elongated modulate 3D migration by directly regulating the nuclear connec- shape was not significantly different from that of Lmna1/1 cells in the tions and organization of a subset of actin filament bundles attached elongated shape (data not shown), providing additional evidence to the nuclear envelope, the perinuclear actin cap26–28. This three- that the difference in speed between Lmna2/2 and Lmna1/1 cells dimensional version of the recently characterized perinuclear actin stems from their difference in protrusion activity. cap observed in a wide range of human and rodent cells on 2D Protrusion activity is driven by actin filament re-organization; substrates28 in turn directs the formation and dynamics of pseudo- therefore to understand the observed differences in protrusion activ- podial protrusions, the main protrusions that control the ability of a ity, we investigated the actin filament organization of Lmna2/2 and cell to pull on and remodel its surrounding matrix. A simple mech- Lmna1/1 cells in 3D matrix. Actin filament organization of Lmna1/1 anical model suggests why the nucleus and nucleo-cytoskeleton con- MEFs was not overtly different from that of Lmna2/2 MEFs on 2D nections play no significant role in 2D migration, but are central in collagen substrates, with the exception of the perinuclear actin cap, a 3D migration. contractile actin filament structure that wraps around the nucleus and shapes it26–28, which was absent in Lmna2/2 MEFs (Fig. 2, A and Results B). Moreover, our previous work has shown that the number, size, Three-dimensional, not two-dimensional, cell migration depends and shape of both focal adhesions were identical in these two cell lines, when they were placed on conventional flat substrates25. on nuclear lamin A/C. Here, we investigate the potential role of 1/1 2/2 lamin A/C in the spontaneous migration of fibroblasts, which in However, confocal light microscopy of Lmna and Lmna vivo involves individual cells moving within a 3D collagen I-rich MEFs embedded in 3D collagen I matrix revealed drastic differences 29 2/2 in actin filament
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