Cells sense their physical environment through mechanotransduction-that is, by translating mechanical forces and deformations into biochemical signals such as changes in intracellular calcium concentration or activation of diverse signalling pathways. In turn, these signals can adjust cellular and extracellular structure. This mechanosensitive feedback modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis and is critical for organ development and homeostasis. Consequently, defects in mechanotransduction-often caused by mutations or misregulation of proteins that disturb cellular or extracellular mechanics-are implicated in the development of a wide array of diseases, ranging from muscular dystrophies and cardiomyopathies to cancer progression and metastasis.Mechanotransduction describes the cellular processes that translate mechanical stimuli into biochemical signals, thus allowing cells to adapt to their physical environment. Extensive research over the last decades has identified several molecular players involved in cellular mechanotransduction (Box 1); however, many components, and especially the identity of the primary mechanosensor(s), remain incompletely defined.Research in mechanotransduction has often focused on sensory cells, such as hair cells in the inner ear. These specialized cells often have evolved specific cellular structures ( Fig. 1) that are tailored to transduce mechanical inputs into biochemical signals (for example, by opening ion channels in response to applied forces) and thus provide a good model to study cellular mechanosensing. Subsequently, it has become apparent that mechanotransduction signalling has a critical role in the maintenance of many mechanically stressed tissues such as muscle, bone, cartilage, and blood vessels; consequentially, research has expanded to diverse celltypes such as myocytes, endothelial cells, and vascular smooth muscle cells. Mechanotransduction is now emerging to be involved in a much broader range of cellular functions, not just in a subset of specialized cells and tissues. For example, stem-cell differentiation can be steered towards specific fates based on the geometry and stiffness of the substrate on which the cells are grown on 1 , and intercellular physical interactions such as tension and adhesion might be as important in embryonic development as concentration gradients of morphogenic factors (see the Review by Wozniak and Chen in this issue.)In this Review, we discuss how mutations and modifications that interfere with normal mechanotransduction and cellular sensitivity to mechanical stress could be implicated in a wide spectrum of diseases that range from loss of hearing to muscular dystrophies and cancer (Table 1). Many of these diseases share few similarities at first sight. How could muscular dystrophies be related to atherosclerosis or kidney failure? In the following, we will highlight some of these disorders and discuss how they could be traced back, at least in part, to defects in mec...

Maintaining physical connections between the nucleus and the cytoskeleton is important for many cellular processes that require coordinated movement and positioning of the nucleus. Nucleo-cytoskeletal coupling is also necessary to transmit extracellular mechanical stimuli across the cytoskeleton to the nucleus, where they may initiate mechanotransduction events. The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, formed by the interaction of nesprins and SUN proteins at the nuclear envelope, can bind to nuclear and cytoskeletal elements; however, its functional importance in transmitting intracellular forces has never been directly tested. This question is particularly relevant since recent findings have linked nesprin mutations to muscular dystrophy and dilated cardiomyopathy. Using biophysical assays to assess intracellular force transmission and associated cellular functions, we identified the LINC complex as a critical component for nucleo-cytoskeletal force transmission. Disruption of the LINC complex caused impaired propagation of intracellular forces and disturbed organization of the perinuclear actin and intermediate filament networks. Although mechanically induced activation of mechanosensitive genes was normal (suggesting that nuclear deformation is not required for mechanotransduction signaling) cells exhibited other severe functional defects after LINC complex disruption; nuclear positioning and cell polarization were impaired in migrating cells and in cells plated on micropatterned substrates, and cell migration speed and persistence time were significantly reduced. Taken together, our findings suggest that the LINC complex is critical for nucleo-cytoskeletal force transmission and that LINC complex disruption can result in defects in cellular structure and function that may contribute to the development of muscular dystrophies and cardiomyopathies.A stable connection between the nucleus and cytoskeleton is required for a wide range of physiological functions such as cell migration or nuclear positioning. Two recently discovered major molecular components involved in nucleo-cytoskeletal coupling are nesprin and SUN proteins, nuclear envelope transmembrane protein families that form a bridge across the nuclear envelope. SUN1 and SUN2 are retained at the inner nuclear membrane by their interaction with lamins, nuclear pore complex proteins, and the nuclear interior, whereas their conserved C-terminal SUN domain extends into the perinuclear space (1-3). Here, they interact with the highly conserved C-terminal KASH domain of nesprins located at the nuclear envelope. Four nesprin genes have been identified to date, many of them containing diverse isoforms as a result of alternate initiation and splicing sites. The largest isoforms of nesprins-1 and -2 contain an N-terminal actin-binding domain, enabling them to interact with cytoplasmic actin filaments (4, 5). Through spectrin-repeat-mediated interactions with kinesin and/or dynein subunits, nesprins-1 and -2 can also connect to microtubules (6...

Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery-Dreifuss Muscular Dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison-Gilford progeria syndrome (HGPS).1 The majority of LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and disturbed interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes.1 We report here that lamin A/C-deficient (Lmna−/−) and Lmna N195K mutant cells have impaired nuclear translocation and downstream signaling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function.2 Disturbed nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna−/− and N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease etiology for the cardiac phenotype in many laminopathies, whereby lamins A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.