Nesprin 1 is critical for nuclear positioning and anchorage

Jianlin Zhang,Ling T Guo,G Diane Shelton,Richard L Lieber,Yusu Gu,Amanda Felder,Yujie Liu,Stephan Lange,Kirk L Peterson,Ju Chen,Nancy D Dalton,Andrew P Mizisin

doi:10.1093/hmg/ddp499

Abstract

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.

Highlights

Emery-Dreifuss muscular dystrophy (EDMD) is a form of muscular dystrophy characterized by progressive skeletal muscle weakness, with associated muscle contractures and variable cardiac defects [1]
Since it has been shown that there are Nesprin 1 splicing isoforms without the KASH domain [26], and to ensure that all isoforms of Nesprin 1 containing C-terminal domains [5] would be ablated, a construct was designed to target a C-terminal exon that is shared by all Nesprin 1 isoforms containing the C-terminal SR region with or without KASH domain (Supplementary Material, Fig. S1A and S2)
We found that young Nesprin 12/2 mice of both sexes experienced growth retardation, increased variability in body weight and decreased exercise tolerance compared with wild-type animals

Summary

Introduction

Emery-Dreifuss muscular dystrophy (EDMD) is a form of muscular dystrophy characterized by progressive skeletal muscle weakness, with associated muscle contractures and variable cardiac defects [1]. Forty percent of patients with EDMD have been shown to have mutations in either Emerin or Lamin A/C (LMNA), two genes encoding proteins localized to the inner nuclear membrane (INM) and its underlying lamina, respectively [2]. 60% of EDMD patients do not have mutations in either Emerin or LMNA, suggesting that other genes are involved in EDMD [2]. Recent data suggest that missense mutations in Nesprins 1 and 2 may be involved in the pathogenesis of EDMD [3]. Mutation of Nesprin 1 has been found to be responsible for autosomal recessive arthrogryposis, another disease characterized by progressive muscle weakness [4]

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Conclusion