Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction
Jan Lammerding, … , Colin L. Stewart, Richard T. Lee
Jan Lammerding, … , Colin L. Stewart, Richard T. Lee
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):370-378. https://doi.org/10.1172/JCI19670.
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Article Cell biology

Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction

Abstract

Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C–deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna–/– cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-κB–regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna–/– cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.

Authors

Jan Lammerding, P. Christian Schulze, Tomosaburo Takahashi, Serguei Kozlov, Teresa Sullivan, Roger D. Kamm, Colin L. Stewart, Richard T. Lee

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Nuclear fragility is increased in lamin A/C–deficient cells. (a and b) F...
Nuclear fragility is increased in lamin A/C–deficient cells. (a and b) Fluorescently labeled 70-kDa dextran is excluded from the nucleus following cytoplasmic injection, indicating an intact nuclear membrane in WT (a) and Lmna–/– (b) cells under resting conditions. Scale bar: 20 μm. (c) Nuclear injection at low pressure results in fluorescently labeled dextran contained in the nucleus of WT cells, indicating that the nuclear integrity is preserved during injection. Scale bar: 20 μm. (d) In contrast, nuclear integrity is disrupted in nuclei of Lmna–/– cells even at low pressure, leading to fluorescently labeled dextran escaping into the cytoplasm during injection. Scale bar: 20 μm. (e) Nuclear rupture as a function of increasing injection pressure of dextran microinjection into the nucleus. Zero pressure: cytoplasmic injection at 500 hPa. Low pressure: nuclear injection at 10–20 hPa (**84.7% ± 4.24% vs. 9.5% ± 4.53% intact nuclei for WT and Lmna–/– cells, respectively; P < 0.0001, n = 72 [WT], 42 [Lmna–/–]). Medium pressure: nuclear injection at 100–500 hPa (*40.4% ± 7.16% vs. 9.5% ± 4.53% intact nuclei for WT and Lmna–/– cells respectively; P < 0.01, n = 47 [WT], 31 [Lmna–/–]). High pressure: nuclear injection at 1,500 hPa; all cells showed nuclear rupture.