The Cellular Mastermind(?)—Mechanotransduction and the Nucleus

Kaminski, Ashley; Fedorchak, Gregory R.; Lammerding, Jan

doi:10.1016/b978-0-12-394624-9.00007-5

Cited by 32 publications

(28 citation statements)

References 214 publications

(292 reference statements)

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“…These signaling pathways were previously shown to change in response to external stress application on cultured cells (3)(4)(5), providing additional confirmation to our results.…”

Section: Discussionsupporting

confidence: 91%

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Molecular dissection of the cellular response to mechanical stress

Zuela-Sopilniak¹,

Dorfman²,

Gruenbaum³

2019

Preprint

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The response of cells to mechanical stress is crucial for many cellular functions, yet its molecular mechanisms are not yet fully understood. Previous studies of the cellular response to mechanical stress were performed on cultured cells or isolated muscle fibers devoid of cell and/or tissue contexts. Thus, the emerging results were limited to the specific cell types or tissues analyzed and dependent on the growth matrix elasticity. In the present study, we looked for changes in early gene expression in response to mechanical whole body stretching of living C. elegans. Our transcriptome analysis revealed upregulation of genes involved in cuticle development, stress response and several signaling pathways such as WNT, TGFβ, AMPK and Hedgehog signaling. These findings indicate that protecting against mechanical insults entails providing additional support to the mechanically resilient protective cuticle, and that proper recovery from mechanical stretching requires an intact Hedgehog signaling pathway. Recent findings suggest an important role for the nuclear lamina in mediating cellular mechanical response. The nuclear lamina is composed mainly of lamins, which are nuclear intermediate filament-type proteins needed, among other functions to maintain nuclear integrity. One particular area of interest are laminopathies, which are caused by mutations in lamin. Stretched animals expressing the Emery Dreifuss Muscular Dystrophy (EDMD) linked L535P lamin mutation, showed further upregulation of cytoskeleton organization, cellular respiration and mitochondrial protein-unfolding stress response genes, most likely to compensate for aberrant muscle tissue function. These findings provide a broad multi-dimensional picture of the in vivo genetic response of live animals to 3 mechanical stress, highlighting previously unreported mechano-sensitive genes and molecular pathways. essentially as described in [21]. In short, Quality control was performed on the raw reads with FastQC (v0.11.2, http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Reads were filtered and quality-trimmed at both ends, using in-house Perl scripts. SL1 and SL2 sequences were removed from the 5' end using cutadapt (version 1.7.1, http://cutadapt.readthedocs.org/en/stable/). The adapter sequence was then similarly trimmed from the 3' end. The remaining reads were filtered for reads that were shorter than 15 nucleotides as well as reads with very low quality, using the fastq_quality_filter program of the FASTX package (version 0.0.14, http://hannonlab.cshl.edu/fastx_toolkit/).The processed fastq files were aligned to the C. elegans genome (version WBcel235) using TopHat (v2.0.13). The Cufflinks package (v2.2.1) was used for quantification, normalization and differential expression. The cummeRbund package (version 2.8.2) and in-house R scripts were used to visualize results.Comparison of global expression, as well as background expression level estimation between samples was measured using FPKM distributions.Differential expression was calculated with c...

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“…These signaling pathways were previously shown to change in response to external stress application on cultured cells (3)(4)(5), providing additional confirmation to our results.…”

Section: Discussionsupporting

confidence: 91%

“…Also affected were processes ranging from protein conformation and assembly, to mechano-sensitive transcription factors (YAP and TAZ) localization to the nucleus [1,2]. In addition to the MAPK pathway, other pathways such as WNT signaling, which can affect proliferation and growth, and TGF-ᵦ responded to an external force [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Molecular dissection of the cellular response to mechanical stress

Zuela-Sopilniak¹,

Dorfman²,

Gruenbaum³

2019

Preprint

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“…We then hypothesized that the observed nuclear actin response involves the nucleoskeleton because this structure has recently been shown to be critically involved in mechanosensing and intracellular force transmission via the LINC complex (21)(22)(23). The LINC complex provides a physical link between the cytoskeleton and the nuclear envelope (24).…”

Section: Resultsmentioning

confidence: 99%

Nuclear F-actin Formation and Reorganization upon Cell Spreading

Plessner

Melak

Chinchilla

et al. 2015

Journal of Biological Chemistry

221

232

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Background: Nuclear actin dynamics may function during basic cellular processes such as adhesion, differentiation, cell shape, and motility. Results: Integrin signaling induces nuclear actin polymerization via the LINC complex in response to fibronectin stimulation or cell spreading. Conclusion: Nuclear actin reorganization occurs during cell spreading and fibronectin stimulation. Significance: This may have important implications for understanding mechanotransduction and nuclear plasticity for matrixdirected differentiation.

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“…Shearing isolated nuclei causes partial unfolding of lamin A/C, exposing cryptic binding sites that could initiate mechanotransduction events [41]. Furthermore, changes in the mechanical microenvironment and force application to intact cells can induce chromatin remodeling [71,72] and dissociation of nuclear protein complexes [73], which could affect both nuclear deformability and gene expression (see [74] and [75] for a detailed discussion of nuclear mechanotransduction). While these reports suggest that nuclear deformation during 3-D migration could impact nuclear organization, chromatin remodeling, and gene expression, direct experimental evidence for this hypothesis is still missing.…”

Section: Biological Consequences Of Nuclear Deformation During 3-d Cementioning

confidence: 99%

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

McGregor

Hsia

Lammerding

2016

Current Opinion in Cell Biology

Self Cite

190

152

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From embryonic development to cancer metastasis, cell migration plays a central role in health and disease. It is increasingly becoming apparent that cells migrating in three-dimensional (3-D) environments exhibit some striking differences compared with their well-established 2-D counterparts. One key finding is the significant role the nucleus plays during 3-D migration: when cells move in confined spaces, the cell body and nucleus must deform to squeeze through available spaces, and the deformability of the large and relatively rigid nucleus can become rate-limiting. In this review, we highlight recent findings regarding the role of nuclear mechanics in 3-D migration, including factors that govern nuclear deformability, and emerging mechanisms by which cells apply cytoskeletal forces to the nucleus to facilitate nuclear translocation. Intriguingly, the ‘physical barrier’ imposed by the nucleus also impacts cytoplasmic dynamics that affect cell migration and signaling, and changes in nuclear structure resulting from the mechanical forces acting on the nucleus during 3-D migration could further alter cellular function. These findings have broad relevance to the migration of both normal and cancerous cells inside living tissues, and motivate further research into the molecular details by which cells move their nuclei, as well as the consequences of the mechanical stress on the nucleus.

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The Cellular Mastermind(?)—Mechanotransduction and the Nucleus

Cited by 32 publications

References 214 publications

Molecular dissection of the cellular response to mechanical stress

Molecular dissection of the cellular response to mechanical stress

Nuclear F-actin Formation and Reorganization upon Cell Spreading

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

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