Stroud Matthew J, Feng Wei, Zhang Jianlin, Veevers Jennifer, Fang Xi, Gerace Larry, Chen Ju
Department of Medicine, University of California, San Diego, La Jolla, CA.
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA.
J Cell Biol. 2017 Jul 3;216(7):1915-1924. doi: 10.1083/jcb.201612128. Epub 2017 May 22.
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.
细胞核在细胞内的位置由核骨架与细胞骨架连接复合体（LINC复合体）和细胞骨架之间的相互作用控制。在许多肌肉疾病中会出现核定位缺陷和细胞核异常聚集的情况，且这些情况与肌肉功能障碍相关。Nesprin 1有多种亚型，是LINC复合体的一个组成部分，对骨骼肌中的核定位和锚定至关重要，并且被认为在细胞核与肌动蛋白之间提供了关键联系。然而，以往的研究尚未确定是哪种亚型发挥这一作用。为阐明这一点，我们培育了一系列Nesprin 1突变小鼠。我们发现Nesprin 1的肌动蛋白结合结构域并非必需，而缺乏肌动蛋白结合结构域的Nesprin 1α2对出生后的生存能力、核定位和骨骼肌功能至关重要。此外，我们还发现驱动蛋白1在Nesprin 1α2基因敲除小鼠的纤维中发生了移位，这表明这种相互作用可能在肌细胞核定位和功能性骨骼肌中发挥重要作用。
