RESEARCH HIGHLIGHTS

MECHANOTRANSDUCTION Lamin A for tension relief The extracellular tension (or stress) The authors also identified the serum that a experiences influences its response factor (SRF) pathway (which behaviour, for example during dif- affects the ) and the ferentiation. Discher and colleagues factor Yes-associated have identified the 1 (YAP1) as potential effector­s protein lamin A as a ‘mechanostat’ of lamin A. factor that is upregulated in response LMNA transcription in this to physical stress and alters the prop- context was found to be controlled erties of the nucleus as well as gene by retinoic acid signalling, as expression. chromatin immunoprecipitation The authors reasoned that specific analysis showed that retinoic acid factors must respond to changes in nuclear receptors bound to LMNA. extracellular matrix (ECM) stiffness Moreover, lamin A levels responded and so analysed the proteomes of to changes in retinoic acid signal- different human and mouse tissues ling, an effect that was increased in to identify possible candidates. They cells on stiff matrix relative to soft observed that levels of lamin A (but matrix and was important for MSC not B-type lamin) globally increased differentiation control. Lamin A in stiff tissues relative to soft tissues knockdown also reduced the levels and scaled with tissue elasticity and nuclear translocation of retinoic (equivalent to stiffness). Mass spec- acid receptors, suggesting that it trometry analysis also showed that might participate in its own negative the conformation and phosphoryla- feedback control. tion of lamin A changed in response Interestingly, increased lamin A to altered extracellular stress, the levels prevented distortion of the latter of which would be consistent nucleus in response to physical stress with reduced lamin A turnover. and increased nuclear viscosity. Next, the authors asked Thus, the authors conclude that whether the changes in lamin A lamin A acts as a mechanostat that occur in response to altered facto­r in cells, and that its increased ECM stiffness are relevant for levels in response to extracellular cell differentiation. It is known tension makes the nucleus more that matrix elasticity can determine resistant to deformation. This might mesenchymal stem cell (MSC) line- ensure that chromatin organization age differentiation, with a soft matrix is not perturbed when tissues experi- favouring the formation of fat and ence stress and may be fundamental a stiff matrix the formation for normal development. of bone. After depletion Alison Schuldt of lamin A, the formation of fat on soft matrix increased, ORIGINAL RESEARCH PAPER Swift, J. et al. whereas overexpression of Nuclear lamin-A scales with tissue stiffness and lamin A on stiff matrix enhances matrix-directed differentiation. Science increased osteogenesis. http://dx.doi.org/10.1126/science.1240104 (2013)

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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 14 | OCTOBER 2013

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