Force-Induced Adsorption and Anisotropic Growth of Focal Adhesions

Besser, Achim; Safran, S. A.

doi:10.1529/biophysj.105.074377

Cited by 109 publications

(138 citation statements)

References 31 publications

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“…Actin can return to the basal state through depolymerization within a few minutes of poststimulation (35). It is known that mechanical tension/stretch or cell substrate stiffness promotes focal adhesion clustering, increased actin polymerization, and cell stiffness (26,(36)(37)(38)(39)(40)(41). The release of tension through myosin II inhibition using blebbistatin leads to actin depolymerization (42).…”

Section: Discussionmentioning

confidence: 99%

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Siechen¹,

Yang

Chiba

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

153

145

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Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynaptic cell. Our in vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored when mechanical tension is applied to the severed end of the axon. Clustering increases when intact axons are stretched mechanically by pulling the postsynaptic muscle. Using micro mechanical force sensors, we find that embryonic axons that have formed neuromuscular junctions maintain a rest tension of Ϸ1 nanonewton. If the rest tension is perturbed mechanically, axons restore the rest tension either by relaxing or by contracting over a period of Ϸ15 min. Our results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation and synaptic plasticity.T he accumulation of neurotransmitter containing vesicles at the presynaptic terminal is essential for neural communication. On the arrival of an action potential at the terminal, neurotransmitters are released through exocytosis of the vesicles. The transmitters excite the postsynaptic terminal in a millisecond time frame (1). The amount of neurotransmitter release for a given action potential depends on several factors including how frequently the synapse has been used. This usage dependent plasticity is believed to be the basis of memory and learning (2). Despite a wealth of knowledge on the molecular components of the synapse (3, 4) and the modulation of the postsynaptic machinery during long-term potentiation and depression (5-7), the mechanism of vesicle accumulation at the presynaptic terminal and regulation of neurotransmission in a usage-dependent manner remains unclear (8). There is increasing experimental evidence suggesting that the mechanical microenvironment has a significant influence on a variety of cell functions including gene expression, cell growth and morphology, cytoskeletal organization, and apoptosis (9-13). Our in vivo experiments reveal that mechanical tension in axons plays a key role in vesicle accumulation.We examine the neuromuscular synapse within live embryos of Drosophila melanogaster (14) (Fig. 1A). In Drosophila, an aCC (anterior corner cell) pioneer motoneuron extends a single axon and invariably innervates its target, muscle1. A pair of aCC motoneurons occurs in every segment of the embryo, and their development is highly stereotyped. The first contact between the aCC axon and muscle1 occurs at hour 14 of embryogenesis, ...

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Section: Discussionmentioning

confidence: 99%

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Siechen¹,

Yang

Chiba

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

153

145

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“…Because this passive strengthening and ab initio formation of domains under force occurs on time scales that are considerably faster than the active cytoskeletal response, we see it as a strong candidate for the elusive force-sensor (3)(4)(5)(6)(7)(8), which triggers the activation of signaling pathways leading to force-dependent regulation of adhesion in living cells. This passive sensing requires only an intact cell membrane with mobile adhesion proteins and should be noticeable even before proper focal adhesions or stress-fibers are formed, which indeed seems to be the case, not only in the motile cells capable of rapid adhesion and translation (36) but also in focal-adhesion forming cells (4).…”

Section: Statistical Elastic Theory and Discussionmentioning

confidence: 99%

“…Under force, the adhesion domains grow (3) (a phenomenon called mechanoresponse, which is also related to mechanosensing, the ability of cells to sense and respond to rigidity) presumably by applying internal forces that interrogate the substrate (4). Forceinduced strengthening is concomitant with the stiffening of the cytoskeleton (3,5,6), leading to the widespread belief that active regulation of the cytoskeleton is solely responsible for mechanoresponse (3,(5)(6)(7)(8)(9). However, this actively driven cytoskeletal remodeling due to external mechanical stimulus is expected to occur over time scales of minutes (4).…”

mentioning

confidence: 99%

Force-induced growth of adhesion domains is controlled by receptor mobility

Smith

Sengupta

Goennenwein

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

134

173

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In living cells, adhesion structures have the astonishing ability to grow and strengthen under force. Despite the rising evidence of the importance of this phenomenon, little is known about the underlying mechanism. Here, we show that force-induced adhesion-strengthening can occur purely because of the thermodynamic response to the elastic deformation of the membrane, even in the absence of the actively regulated cytoskeleton of the cell, which was hitherto deemed necessary. We impose pN-forces on two fluid membranes, locally pre-adhered by RGD-integrin binding. One of the binding partners is always mobile whereas the mobility of the other can be switched on or off. Immediate passive strengthening of adhesion structures occurs in both cases. When both binding partners are mobile, strengthening is aided by lateral movement of intact bonds as a transient response to force-induced membrane-deformation. By extending our microinterferometric technique to the suboptical regime, we show that the adhesion, as well as the resistance to force-induced de-adhesion, is greatly enhanced when both, rather than only one, of the binding partners are mobile. We formulate a theory that explains our observations by linking the macroscopic shape deformation with the microscopic formation of bonds, which further elucidates the importance of receptor mobility. We propose this fast passive response to be the first-recognition that triggers signaling events leading to mechanosensing in living cells.cell adhesion under force ͉ dynamic reflection interference contrast microscopy ͉ magnetic tweezers ͉ mobile integrin-RGD bonds ͉ model systems T he formation of adhesion domains is a ubiquitous event in the early stages of cell adhesion. The domains are agglomerates of bonds formed between receptors and counterreceptors (1). For cell-cell contact, before adhesion, both binding partners are mobile, whereas for cells adhering to the extracellular matrix, the counterreceptors are fixed. In the late, actively regulated stage of adhesion, the actin cytoskeleton couples to the adhesion domains (2). Under force, the adhesion domains grow (3) (a phenomenon called mechanoresponse, which is also related to mechanosensing, the ability of cells to sense and respond to rigidity) presumably by applying internal forces that interrogate the substrate (4). Forceinduced strengthening is concomitant with the stiffening of the cytoskeleton (3, 5, 6), leading to the widespread belief that active regulation of the cytoskeleton is solely responsible for mechanoresponse (3, 5-9). However, this actively driven cytoskeletal remodeling due to external mechanical stimulus is expected to occur over time scales of minutes (4). Although it has been mooted previously that, at shorter time scales, the response is dominated by the physical properties of the membrane (1, 10), the force-response of cells over subsecond time scales has rarely been explored. At the same time, several studies have shown that, even in the absence of force, the adhesion is enhanced if both the liga...

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“…Recent evidence suggests that the correlation between adhesion size and traction is strongest during the assembly process (Stricker et al, 2011) and requires an intact signaling system (Prager-Khoutorsky et al, 2011). Mature focal adhesions are typically elongated in the direction of the attached stress fibers, an effect that might be a direct result of the force transmitted through the stress fibers (Nicolas et al, 2004;Shemesh et al, 2005;Besser and Safran, 2006;Walcott et al, 2011). Mature focal adhesions provide stable adhesive interactions between the cell and the ECM over 10-20-minute time scales.…”

Section: Measuring Cellular Forcementioning

confidence: 99%

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

Schwarz

Gardel

2012

Journal of Cell Science

305

317

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SummaryMany essential cellular functions in health and disease are closely linked to the ability of cells to respond to mechanical forces. In the context of cell adhesion to the extracellular matrix, the forces that are generated within the actin cytoskeleton and transmitted through integrin-based focal adhesions are essential for the cellular response to environmental clues, such as the spatial distribution of adhesive ligands or matrix stiffness. Whereas substantial progress has been made in identifying mechanosensitive molecules that can transduce mechanical force into biochemical signals, much less is known about the nature of cytoskeletal force generation and transmission that regulates the magnitude, duration and spatial distribution of forces imposed on these mechanosensitive complexes. By focusing on cellmatrix adhesion to flat elastic substrates, on which traction forces can be measured with high temporal and spatial resolution, we discuss our current understanding of the physical mechanisms that integrate a large range of molecular mechanotransduction events on cellular scales. Physical limits of stability emerge as one important element of the cellular response that complements the structural changes affected by regulatory systems in response to mechanical processes.

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Force-Induced Adsorption and Anisotropic Growth of Focal Adhesions

Cited by 109 publications

References 31 publications

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

Force-induced growth of adhesion domains is controlled by receptor mobility

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

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