Human Molecular Genetics Advance Access published online on September 19, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm255
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells
1 Department of Cell and Developmental Biology, University of Würzburg, 97074 Würzburg, Germany 2 Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany 3 Ernst-Moritz-Arndt-University, Institute of Human Genetics, 17487 Greifswald, Germany 4 Department of Human Genetics, University of Würzburg, Germany 5 Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong 6 Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany 7 Department of Biological Sciences, The School of Biological and Biomedical Sciences, The University of Durham, Durham, UK
* To whom correspondence should be addressed: I. Karakesisoglou; Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, D-50931 Cologne, Germany, Tel.: 49-221-478-6987; Fax: 49-221-478-6979; E-mail: iakowos.karakesisoglou{at}uni-koeln.de and Marie-Christine Dabauvalle; Department of Cell and Developmental Biology, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, Tel.: 49-931-888 4273, Fax.: 49-931-888 4252, E-mail: mcd{at}biozentrum.uni-wuerzburg.de
Received May 15, 2007; Revised September 2, 2007; Accepted September 2, 2007
The S143F lamin A/C point mutation causes a phenotype combining features of myopathy and progeria. We demonstrate here that patient dermal fibroblast cells have dysmorphic nuclei containing numerous blebs and lobulations, which progressively accumulate as cells age in culture. The lamin A/C organisation is altered, showing intranuclear and nuclear envelope aggregates and presenting often a honeycomb appearance. Immunofluorescence microscopy showed that nesprin-2 C-terminal isoforms and LAP2
were recovered in the cytoplasm, whereas LAP2ß and emerin were unevenly localised along the nuclear envelope. In addition, the intranuclear organisation of acetylated histones, histone H1 and the active form of RNA polymerase II were markedly different in patient cells. A subpopulation of mutant cells, however, expressing the 800 kDa nesprin-2 giant isoform did not show an overt nuclear phenotype. Ectopic expression of p.S143F lamin A in fibroblasts recapitulates the patient cell phenotype, whereas no effects were observed in p.S143F LMNA keratinocytes, which highly express nesprin-2 giant. Overexpression of the mutant lamin A protein had a more severe impact on the nuclear envelope of nesprin-2 giant deficient fibroblasts when compared to wild type. In summary, our results suggest that the p.S143F lamin A mutation affects nuclear envelope architecture and composition, chromatin organisation, gene expression and transcription. Furthermore, our findings implicate a direct involvement of the nesprins in laminopathies and propose nesprin-2 giant as a structural reinforcer at the nuclear envelope.
# These authors contributed equally to the paper.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Luke, H. Zaim, I. Karakesisoglou, V. M. Jaeger, L. Sellin, W. Lu, M. Schneider, S. Neumann, A. Beijer, M. Munck, et al. Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin J. Cell Sci., June 1, 2008; 121(11): 1887 - 1898. [Abstract] [Full Text] [PDF]
|
|