Mechanotransduction from the ECM to the genome: Are the pieces now in place?

Gieni, Randall S.; Hendzel, Michael J.

doi:10.1002/jcb.21364

Cited by 132 publications

(116 citation statements)

References 209 publications

(274 reference statements)

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“…Specificity of TGF‐β1‐binding was confirmed by competition with unlabeled TGF‐β1. To further investigate the connection between reduced size/mechanical force and specific down‐regulation of TβRII, we treated fibroblasts in constrained collagen matrices with latrunculin‐A (Lat‐A), which rapidly blocks actin polymerization (Gieni & Hendzel, 2008). As expected, disruption of the actin cytoskeleton resulted in reduced fibroblast size (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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Section: Resultsmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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“…Lamins are nuclear proteins, but are known to be mechanically linked to the cytoskeleton via nuclear-envelope-spanning complexes of SUN-and KASH-domain proteins (27)(28)(29). Because Klarsicht, a KASH protein, interacts with the Drosophila B-type lamin and is required for nuclear movement in photoreceptor cells (26), it seems possible that neuronal migration in mammals could also involve SUN-and KASH-domain proteins.…”

Section: Discussionmentioning

confidence: 99%

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Coffinier¹,

Chang²,

Nobumori³

et al. 2010

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

145

209

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Nuclear lamins are components of the nuclear lamina, a structural scaffolding for the cell nucleus. Defects in lamins A and C cause an array of human diseases, including muscular dystrophy, lipodystrophy, and progeria, but no diseases have been linked to the loss of lamins B1 or B2. To explore the functional relevance of lamin B2, we generated lamin B2-deficient mice and found that they have severe brain abnormalities resembling lissencephaly, with abnormal layering of neurons in the cerebral cortex and cerebellum. This neuronal layering abnormality is due to defective neuronal migration, a process that is dependent on the organized movement of the nucleus within the cell. These studies establish an essential function for lamin B2 in neuronal migration and brain development.brain | lissencephaly | neuronal migration | nuclear envelope | nuclear lamina T he nuclear lamina is an intermediate filament meshwork lying beneath the inner nuclear membrane that provides a structural scaffolding for the nucleus (1). The lamina is also important for other processes, including gene transcription, chromatin organization, nuclear pore distribution, nuclear envelope assembly, and tethering of the nucleus to the cytoskeleton (1, 2). The main components of the nuclear lamina are nuclear lamins, a class of intermediate filament proteins that is generally divided into two groups, A-type (lamins A and C) and B-type (lamins B1 and B2) (3, 4). Lamins A and C are produced from LMNA by alternative splicing, whereas lamins B1 and B2 are encoded by distinct genes, LMNB1 and LMNB2, respectively. Lamins B1 and B2 are expressed in all cells and throughout development, whereas lamins A and C are expressed in differentiated cells, beginning at midgestation (3).Interest in the nuclear lamins has intensified with the discovery that over a dozen human diseases, including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria, are caused by mutations in LMNA (5-7). To date, more than 340 missense, nonsense, frameshift, and splicing mutations have been identified (5). In contrast, no human diseases have been linked to these types of mutations in LMNB1 and LMNB2, and, so far, the only clear-cut association between B-type lamins and disease has been the finding of LMNB1 gene duplications in autosomal-dominant leukodystrophy (8).The paucity of "lamin B diseases" is probably not due to complete redundancy of lamins B1 and B2, as Lmnb1-deficient mice are small during embryonic development and die soon after birth with defects in lungs and bones (9). Also, Lmnb1-deficient fibroblasts display misshapen cell nuclei, aneuploidy, and early senescence (9). To further examine the functional importance of the B-type lamins, we generated Lmnb2-deficient mice.

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“…These changes can open or close areas of DNA near to the transcription site (Dalby et al, 2007;Gieni and Hendzel, 2008). With this in mind, it seemed appropriate to determine whether the stiffness of the substrate influences the transcriptional activity in the nucleus.…”

Section: Uncoupled Contribution From the Substrate Elasticity To The mentioning

confidence: 99%

“…Major cellular events take place within the nucleus, including replication, messenger RNA synthesis and processing, and ribosome subunit biogenesis. How mechanical matrix information transmitted through the cytoskeleton can affect both structure and function within the nucleus is a matter of great debate (Gieni and Hendzel, 2008). 'Tensegrity' models postulated how mechanical forces, generated through cell-ECM interactions via focal adhesions (FAs) could impact cytoskeletal and nuclear morphology and ultimately induce changes in the pattern of gene expression (Wang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Selective and uncoupled role of substrate elasticity in the regulation of replication and transcription in epithelial cells

Kocgozlu

Lavalle

Koenig

et al. 2010

Journal of Cell Science

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SummaryActin cytoskeleton forms a physical connection between the extracellular matrix, adhesion complexes and nuclear architecture. Because tissue stiffness plays key roles in adhesion and cytoskeletal organization, an important open question concerns the influence of substrate elasticity on replication and transcription. To answer this major question, polyelectrolyte multilayer films were used as substrate models with apparent elastic moduli ranging from 0 to 500 kPa. The sequential relationship between Rac1, vinculin adhesion assembly, and replication becomes efficient at above 200 kPa because activation of Rac1 leads to vinculin assembly, actin fiber formation and, subsequently, to initiation of replication. An optimal window of elasticity (200 kPa) is required for activation of focal adhesion kinase through auto-phosphorylation of tyrosine 397. Transcription, including nuclear recruitment of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), occurred above 50 kPa. Actin fiber and focal adhesion signaling are not required for transcription. Above 50 kPa, transcription was correlated with v-integrin engagement together with histone H3 hyperacetylation and chromatin decondensation, allowing little cell spreading. By contrast, soft substrate (below 50 kPa) promoted morphological changes characteristic of apoptosis, including cell rounding, nucleus condensation, loss of focal adhesions and exposure of phosphatidylserine at the outer cell surface. On the basis of our data, we propose a selective and uncoupled contribution from the substrate elasticity to the regulation of replication and transcription activities for an epithelial cell model.

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Mechanotransduction from the ECM to the genome: Are the pieces now in place?

Cited by 132 publications

References 209 publications

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Selective and uncoupled role of substrate elasticity in the regulation of replication and transcription in epithelial cells

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