title: 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-kappaB-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.affiliation: Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Teresa
authors.initials: T
authors.lastname: Sullivan
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005347:Fibroblasts; D005434:Flow Cytometry; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D034904:Lamin Type A; D016328:NF-kappa B