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First published online 25 January 2005
doi: 10.1242/jcs.01642
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Research Article |
1 Department of Medicine, ACCI, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK
2 Multi-Imaging Centre, Department of Anatomy, Downing Street, Cambridge, CB2 3DY, UK
3 Division of Medical and Molecular Genetics, GKT Medical School, 8th Floor, Guy's Tower, Guy's Hospital, London, SE1 9RT, UK
4 Randall Centre for the Molecular Mechanism of Cell Function, Kings College, New Hunts House, Guy's Campus, London, SE1 1UL, UK
* Author for correspondence (e-mail: cs131{at}mole.bio.cam.ac.uk)
Accepted 10 November 2004
Nesprin-2 is a multi-isomeric, modular protein composed of variable numbers of spectrin-repeats linked to a C-terminal transmembrane domain and/or to N-terminal paired calponin homology (CH) domains. The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). In SW-13 cells, which lack lamin A/C, nesprin-2 epitopes and emerin were both mislocalized and formed aggregates in the endoplasmic reticulum (ER). The larger isoforms and other CH-domain-containing isoforms co-localize with heterochromatin within the nucleus and are also present at the outer NE and in multiple cytoplasmic compartments. Nesprin-2 isoforms relocalize during in vitro muscle differentiation of C2C12 myoblasts to the sarcomere of myotubes. Immunogold electron microscopy using antibodies specific for three different epitopes detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. In adult skeletal muscle, confocal immunolocalization studies demonstrated that nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. These data suggest that nesprin-2 isoforms form a linking network between organelles and the actin cytoskeleton and thus may be important for maintaining sub-cellular spatial organisation. Moreover, its association at the NE with lamin and emerin, the genes mutated in Emery-Dreifuss muscular dystrophy, suggests a mechanism to explain how disruption of the NE leads to muscle dysfunction.
Key words: Nuclear envelope, Lamin, Actin, Muscle, Sarcoplasmic reticulum
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