title: Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response.
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.
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Indroneal
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore-Morris
authors.affiliation: Department of Bioengineering, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Pfeiffer
authors.affiliation: Department of Bioengineering, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Buchholz
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Ao
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America ; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Stroud
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Larry
authors.initials: L
authors.lastname: Gerace
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America ; Department of Bioengineering, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: McCulloch
authors.affiliation: Department of Medicine, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism; D015530:Nuclear Matrix / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485901:Syne1 protein, mouse; C485903:Syne2 protein, mouse