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Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response

Academic Article
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Overview

authors

  • Banerjee, I.
  • Zhang, J.
  • Moore-Morris, T.
  • Pfeiffer, E.
  • Buchholz, K. S.
  • Liu, A.
  • Ouyang, K.
  • Stroud, M. J.
  • Gerace, Larry
  • Evans, S. M.
  • McCulloch, A.
  • Chen, J.

publication date

  • 2014

journal

  • PLoS Genetics  Journal

abstract

  • Recent interest has focused on the importance of the nucleus and associated nucleoskeleton in regulating changes in cardiac gene expression in response to biomechanical load. Mutations in genes encoding proteins of the inner nuclear membrane and nucleoskeleton, which cause cardiomyopathy, also disrupt expression of a biomechanically responsive gene program. Furthermore, mutations in the outer nuclear membrane protein Nesprin 1 and 2 have been implicated in cardiomyopathy. Here, we identify for the first time a role for the outer nuclear membrane proteins, Nesprin 1 and Nesprin 2, in regulating gene expression in response to biomechanical load. Ablation of both Nesprin 1 and 2 in cardiomyocytes, but neither alone, resulted in early onset cardiomyopathy. Mutant cardiomyocytes exhibited altered nuclear positioning, shape, and chromatin positioning. Loss of Nesprin 1 or 2, or both, led to impairment of gene expression changes in response to biomechanical stimuli. These data suggest a model whereby biomechanical signals are communicated from proteins of the outer nuclear membrane, to the inner nuclear membrane and nucleoskeleton, to result in changes in gene expression required for adaptation of the cardiomyocyte to changes in biomechanical load, and give insights into etiologies underlying cardiomyopathy consequent to mutations in Nesprin 1 and 2.

subject areas

  • Animals
  • Biomechanical Phenomena
  • Cardiomyopathies
  • Cell Nucleus
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mutation
  • Myocardium
  • Myocytes, Cardiac
  • Nerve Tissue Proteins
  • Nuclear Envelope
  • Nuclear Matrix
  • Nuclear Proteins
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Identity

PubMed Central ID

  • PMC3930490

International Standard Serial Number (ISSN)

  • 1553-7404 (Electronic) 1553-7390 (Linking)

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1004114

PubMed ID

  • 24586179
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Additional Document Info

start page

  • e1004114

volume

  • 10

issue

  • 2

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