Interfering with the connection between the nucleus and the cytoskeleton affects nuclear rotation, mechanotransduction and myogenesis.
Mechanical stress controls a broad range of cellular functions. The cytoskeleton is physically connected to the extracellular matrix via integrin receptors, and to the nuclear lamina by the LINC complex that spans both nuclear membranes. We asked here how disruption of this direct link from the cytoskeleton to nuclear chromatin affects mechanotransduction. Fibroblasts grown on flexible silicone membranes reacted to cyclic stretch by nuclear rotation. This rotation was abolished by inhibition of actomyosin contraction as well as by overexpression of dominant-negative versions of nesprin or sun proteins that form the LINC complex. In an in vitro model of muscle differentiation, cyclic strain inhibits differentiation and induces proliferation of C2C12 myoblasts. Interference with the LINC complex in these cells abrogated their stretch-induced proliferation, while stretch increased p38 MAPK and NFkappaB phosphorylation and the transcript levels of myogenic transcription factors MyoD and myogenin. We found that the physical link from the cytoskeleton to the nuclear lamina is crucial for correct mechanotransduction, and that disruption of the LINC complex perturbs the mechanical control of cell differentiation.
Brosig
Michaela
M
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
Ferralli
Jacqueline
J
Gelman
Laurent
L
Chiquet
Matthias
M
Chiquet-Ehrismann
Ruth
R
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics; D051379:Mice; D008858:Microscopy, Phase-Contrast; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D024510:Muscle Development / Q000235:genetics; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012399:Rotation; D013314:Stress, Mechanical; D059008:Time-Lapse Imaging; D019076:Transgenes / Q000235:genetics
D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C464932:SUN1 protein, mouse; C485903:Syne2 protein, mouse; D000205:Actomyosin