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      Nesprin 1α2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle

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          Abstract

          Defects in nuclear positioning occur in muscle diseases and correlate with muscle dysfunction. In this study, Stroud et al. show that nesprin 1α2 is the fundamental nesprin 1 isoform for nuclear positioning, skeletal muscle function, and postnatal viability.

          Abstract

          The position of the nucleus in a cell is controlled by interactions between the linker of nucleoskeleton and cytoskeleton (LINC) complex and the cytoskeleton. Defects in nuclear positioning and abnormal aggregation of nuclei occur in many muscle diseases and correlate with muscle dysfunction. Nesprin 1, which includes multiple isoforms, is an integral component of the LINC complex, critical for nuclear positioning and anchorage in skeletal muscle, and is thought to provide an essential link between nuclei and actin. However, previous studies have yet to identify which isoform is responsible. To elucidate this, we generated a series of nesprin 1 mutant mice. We showed that the actin-binding domains of nesprin 1 were dispensable, whereas nesprin 1α2, which lacks actin-binding domains, was crucial for postnatal viability, nuclear positioning, and skeletal muscle function. Furthermore, we revealed that kinesin 1 was displaced in fibers of nesprin 1α2–knockout mice, suggesting that this interaction may play an important role in positioning of myonuclei and functional skeletal muscle.

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          Nuclear positioning.

          The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain.

            We have generated a transgenic line that expresses the Cre gene product under the regulation of a 12.5 kb upstream regulatory sequence from the Sox2 gene. Using a R26R reporter line, we show that this transgenic line induces recombination in all epiblast cells by embryonic day (E) 6.5 but little or no activity in other extraembryonic cell types at this time. When crossed to a conditional allele of the Sonic hedgehog gene (Shhc), all Sox2Cre;Shhn/Shhc embryos displayed a phenotype indistinguishable from that of the Shh null mutant. Sox2Cre functioned more efficiently in epiblast-mediated recombination than the Mox2Cre (MORE) transgenic line, which has also been shown to drive Cre-mediated recombination exclusively in the embryonic component of the early mouse embryo. Although most MORE; shhh/shhc embryos have a shh hull phenotype, 33% displayed a milder skeletal phenotype, most likely result of incomplete recombination at egg cylinder stages. In agreement with these findings, Sox2Cre was active earlier and Sox2Cre-mediated recombination was more advanced than MORE-mediated recombination at early gastrulation stages. The Sox2Cre line is likely to be more effective in generating complete, epiblast-specific removal of gene activity, and the mosaic activity of the MORE line will be helpful in generating partial loss-of-function phenotypes in the embryo-proper.
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              MAP and Kinesin dependent nuclear positioning is required for skeletal muscle function

              The basic unit of skeletal muscle in all metazoans is the multinucleate myofiber, within which individual nuclei are regularly positioned 1 . The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous muscles diseases 2 , including centronuclear myopathies 3 , but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein Ensconsin(Ens)/MAP7 and Kinesin Heavy Chain (Khc)/Kif5b as essential, evolutionary conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins physically interact and that expression of the Kif5b motor domain fused to the MAP7 microtubule binding domain rescues nuclear positioning defects in MAP7 depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally we demonstrate that myonuclear positioning is physiologically important. Drosophila ens mutant larvae display decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell autonomous fashion.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                03 July 2017
                03 July 2017
                : 216
                : 7
                : 1915-1924
                Affiliations
                [1 ]Department of Medicine, University of California, San Diego, La Jolla, CA
                [2 ]Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
                Author notes
                Correspondence to Ju Chen: juchen@ 123456ucsd.edu
                [*]

                M.J. Stroud and W. Feng contributed equally to this paper.

                M.J. Stroud’s present address is British Heart Foundation Centre of Excellence, Cardiovascular Division, King's College London, London, England, UK.

                Author information
                http://orcid.org/0000-0002-1753-993X
                http://orcid.org/0000-0002-7935-4578
                http://orcid.org/0000-0002-3337-6851
                Article
                201612128
                10.1083/jcb.201612128
                5496623
                28533284
                54014563-4aa5-4bbf-ac00-3cdf9fb25a04
                © 2017 Stroud et al.

                This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

                History
                : 07 January 2017
                : 08 March 2017
                : 18 April 2017
                Funding
                Funded by: American Heart Association, DOI http://dx.doi.org/10.13039/100000968;
                Award ID: 13POST17060120
                Award ID: 16POST30960067
                Funded by: California Institute for Regenerative Medicine, DOI http://dx.doi.org/10.13039/100000900;
                Award ID: TG2-01154
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Funded by: Foundation Leducq, DOI http://dx.doi.org/10.13039/501100001674;
                Award ID: TNE-13CVD04
                Funded by: American Heart Association, DOI http://dx.doi.org/10.13039/100000968;
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: P30 NS047101
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                Cell biology
                Cell biology

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