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From extracellular matrix to cytoskeleton to nucleus: role of direct physical links in gene regulation by mechanical signals

English title From extracellular matrix to cytoskeleton to nucleus: role of direct physical links in gene regulation by mechanical signals
Applicant Chiquet-Ehrismann Ruth
Number 120235
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Cellular Biology, Cytology
Start/End 01.04.2008 - 31.03.2011
Approved amount 399'000.00
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Keywords (10)

mechanical stress; mechanotransduction; extracellular matrix; cytoskeleton; focal adhesion; nuclear membrane; gene regulation; tissue homeostasis; fibroblast; cell culture

Lay Summary (English)

Lead
Lay summary
Mechanical signals are known to regulate the expression of specific genes. It is important to know how connective tissue cells sense strains within the extracellular matrix (ECM) to which they attach, and how they translate this information into adaptive responses. By physical connections between structural components, external mechanical stresses are transmitted to the pericellular ECM, across the cell membrane to the cytoskeleton, and from there all the way to the nucleus. Hence, we hypothesize that mechanical stimuli could be converted into chemical signals not only in focal adhesions at the cell surface but also at other intracellular locations where stresses are high. We propose that such sites are specialized for sensing various modes of mechanical stress. We will test the hypothesis that mechanotransduction arising from different locations within the cell leads to regulation of distinct sets of genes. Mechanical loading is essential for homeostasis and regeneration of muscle, bone and connective tissues. Training by physical exercise as well as physiotherapy are based on this important biological principle. Many pathologies are at least in part caused by abnormally high or low physical stress. Examples are on the one hand hypertension-induced hypertrophy of the heart, overload-induced osteoarthrosis, hypertrophic scarring of skin wounds, or tendinopathies, and on the other hand microgravity or bedrest-induced atrophy of bone, muscle and connective tissue. Moreover, muscular dystrophies manifest the importance of sustaining mechanical loads: defective links between the cytoskeleton and the cell surface or the nucleus, respectively, can cause activity-induced physical damage and consequently myofiber degeneration. Although the importance of mechanical stimuli is widely appreciated, mechanisms by which cells translate them into specific adaptive responses are incompletely understood.We address the problem of cellular mechanotransduction in tissue culture studies. We plate fibroblasts and muscle cells on ECM-coated flexible silicone membranes allowing us to apply mechanical stress to cells by stretching the membranes. Cells will be observed by live imaging during stretching. We plan to examine the function of MAL/MKL1, a transcriptional co-activator that shuttles between the cytoplasm and the nucleus, in gene activation by external cyclic strain. Furthermore, we will test whether a direct physical link between cytoskeleton and nucleus, mediated by the nuclear membrane proteins sun and nesprin, is involved in stretch-dependent gene expression. We will interfere with the function of components potentially involved in mechanotransduction either by knocking down expression by shRNA, or by retroviral transduction of dominant negative constructs. The effects on gene expression will be evaluated by RNA profiling. The promoters of selected mechanoresponsive genes will be isolated and analyzed for cis-acting elements and transcription factor binding.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
135584 From extracellular matrix to cytoskeleton to nucleus: mechanotransduction in cancer progression 01.04.2011 Project funding (Div. I-III)

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