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Human Molecular Genetics Advance Access first published online on October 28, 2009
This version [Corrected Proof] published online on November 9, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp499
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nesprin 1 is critical for nuclear positioning and anchorage

Jianlin Zhang1, Amanda Felder3, Yujie Liu1, Ling T. Guo2, Stephan Lange1, Nancy D. Dalton1, Yusu Gu1, Kirk L. Peterson1, Andrew P. Mizisin2, G. Diane Shelton2, Richard L. Lieber3 and Ju Chen1,*

1 Department of Medicine and 2 Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA and 3 Department of Orthopaedic Surgery and Bioengineering, University of California San Diego and Veterans Affairs Medical Centers, San Diego, CA 92161, USA

* To whom correspondence should be addressed at: Department of Medicine, University of California San Diego, 9500 Gilman Drive, BSB, Room 5025, La Jolla, CA 92093-0613, USA. Tel: +1 8588224276; Fax: +1 8585342069; Email: juchen{at}ucsd.edu

Received August 25, 2009; Revised October 19, 2009; Accepted October 26, 2009

Nesprin 1 is an outer nuclear membrane protein that is thought to link the nucleus to the actin cytoskeleton. Recent data suggest that mutations in Nesprin 1 may also be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy. To investigate the function of Nesprin 1 in vivo, we generated a mouse model in which all isoforms of Nesprin 1 containing the C-terminal spectrin-repeat region with or without KASH domain were ablated. Nesprin 1 knockout mice are marked by decreased survival rates, growth retardation and increased variability in body weight. Additionally, nuclear positioning and anchorage are dysfunctional in skeletal muscle from knockout mice. Physiological testing demonstrated no significant reduction in stress production in Nesprin 1-deficient skeletal muscle in either neonatal or adult mice, but a significantly lower exercise capacity in knockout mice. Nuclear deformation testing revealed ineffective strain transmission to nuclei in muscle fibers lacking Nesprin 1. Overall, our data show that Nesprin 1 is essential for normal positioning and anchorage of nuclei in skeletal muscle.


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