Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices

Wolfenson, Haguy; Meacci, Giovanni; Liu, Shuaimin; Stachowiak, Matthew R.; Iskratsch, Thomas; Ghassemi, Saba; Roca‐Cusachs, Pere; O’Shaughnessy, Ben; Hone, James; Sheetz, Michael P.

doi:10.1038/ncb3277

Cited by 181 publications

(290 citation statements)

References 60 publications

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“…In general, WAVE and the upregulated tropomyosins control in a reciprocal crosstalk the actin filament branching (Bugyi et al, 2010; Krause and Gautreau, 2014); for the latter one distinct roles in neurons for the different isoforms have been described (Schevzov et al, 2012). Interestingly, tropomyosin has been found to regulate mechanotransductive processes via sarcomer-like structures (Wolfenson et al, 2016). srGAPs are essential for the fine-tuning of the neurite leading process branching, modulating neuronal morphogenesis and migration (Pertz et al, 2008; Guerrier et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

Schulte

Ripamonti

Maffioli

et al. 2016

Front. Cell. Neurosci.

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The identification of biomaterials which promote neuronal maturation up to the generation of integrated neural circuits is fundamental for modern neuroscience. The development of neural circuits arises from complex maturative processes regulated by poorly understood signaling events, often guided by the extracellular matrix (ECM). Here we report that nanostructured zirconia surfaces, produced by supersonic cluster beam deposition of zirconia nanoparticles and characterized by ECM-like nanotopographical features, can direct the maturation of neural networks. Hippocampal neurons cultured on such cluster-assembled surfaces displayed enhanced differentiation paralleled by functional changes. The latter was demonstrated by single-cell electrophysiology showing earlier action potential generation and increased spontaneous postsynaptic currents compared to the neurons grown on the featureless unnaturally flat standard control surfaces. Label-free shotgun proteomics broadly confirmed the functional changes and suggests furthermore a vast impact of the neuron/nanotopography interaction on mechanotransductive machinery components, known to control physiological in vivo ECM-regulated axon guidance and synaptic plasticity. Our results indicate a potential of cluster-assembled zirconia nanotopography exploitable for the creation of efficient neural tissue interfaces and cell culture devices promoting neurogenic events, but also for unveiling mechanotransductive aspects of neuronal development and maturation.

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Section: Discussionmentioning

confidence: 99%

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

Schulte

Ripamonti

Maffioli

et al. 2016

Front. Cell. Neurosci.

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“…Bead motion reveals discrete steps after shear force application at threshold pMHC numbers (2 VSV8/K b at the interface). The traces are characteristic of single-molecule motility of motor proteins on cytoskeletal filaments (46). Regular stepping occurs with average displacements and dwells of ∼7.7 nm for the primary peak (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

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

162

197

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T lymphocytes use surface αβ T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction (∼10 pN per TCR molecule) triggers T-cell Ca 2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via ∼8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers.mechanosensor | T-cell receptor | T-cell activation | optical tweezers | cellular force relaxation T he T-cell receptor (TCR) expressed on T lymphocytes of the adaptive immune system is a stout and squat (12-nm wide × 8-nm tall) multisubunit surface complex with a ligand binding moiety that is an αβ disulfide-linked heterodimer buttressed by the associated invariant CD3 subunits (1-3). The αβ chains are each encoded by V and J gene segments and in the case of the β, a D segment as well (4). The clone-specific TCR unique to each T lymphocyte endows mammals with the capacity to detect perturbations in host cellular function resulting from myriad infectious pathogens, physical damage (thermal, irradiation, etc.), or premalignant or malignant cellular transformations while averting strong self-reactivities that could induce autoimmunity (5).Signaling is initiated through ligation of the clonotype by its cognate antigenic peptide bound to an MHC molecule (pMHC) and displayed on the surface of antigen-presenting cells (APCs) (6, 7). Ligation impacts disposition and function of the associated CD3 dimers (CD3 γ, CD3 δ, and CD3ζζ) as well as the transmembrane domains of the TCR heterodimer and CD3 subunits that interdigitate in the membrane to signal into the cytoplasm (8, 9). A cascade of intracellular events involving phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 cytoplasmic domains with subsequent ZAP70 activation and downstream signaling follows (10, 11). Membrane-associated CD8 and CD4 coreceptors, marking cytotoxic T lymphocytes (CTLs) and helper T cells, respectively, function to bring the membrane-anchored Src family tyrosine kinase Lck to the TCR-pMHC complex for the initiation of ITAM phosphorylation. Signaling, in turn, leads to a transient rise of cytosolic Ca 2+ and other biochemical events resulting in transcriptional activation, ultimately resulting in developmental decisions or effector functi...

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“…Quantized micropillar displacements by attached cells appear to be due to tropomyosin-dependent, rigidity-sensing units that operate during the contractile spreading phase 34 . Our results are consistent with a model based on postulated stiffness-dependent strain rates 17 .…”

Section: Discussionmentioning

confidence: 99%

Nanoscale mechanics guides cellular decision making

et al. 2016

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This study used novel, force-limited nanoscale tension gauges to investigate how force and substrate stiffness guide cellular decision-making during initial cell attachment and spreading on deformable substrates. The well-established dependence of cell traction and spreading on substrate stiffness has been attributed to levels of force exerted on molecular components in focal contacts. The molecular tension gauges used in this study enabled direct estimates of threshold, pico Newton forces that instructed decision-making at different stages of cell attachment, spreading, and adhesion maturation. Results show that the force thresholds controlling cellular adhesion and spreading transitions depend on substrate stiffness. Reported findings agree qualitatively with a proposed model that attributes rigidity-dependent differences in cell spreading to stiffness-dependent rates of competing biochemical processes. Moreover, estimated magnitudes of force thresholds governing transitions in cell attachment and spreading, based on these in situ measurements, were in remarkable agreement with prior less direct measurements.

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Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices

Cited by 181 publications

References 60 publications

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

Mechanosensing drives acuity of αβ T-cell recognition

Nanoscale mechanics guides cellular decision making

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