Schulman Victoria K, Folker Eric S, Rosen Jonathan N, Baylies Mary K
Cell and Developmental Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America; Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
PLoS Genet. 2014 Dec 18;10(12):e1004880. doi: 10.1371/journal.pgen.1004880. eCollection 2014 Dec.
Highlighting the importance of proper intracellular organization, many muscle diseases are characterized by mispositioned myonuclei. Proper positioning of myonuclei is dependent upon the microtubule motor proteins, Kinesin-1 and cytoplasmic Dynein, and there are at least two distinct mechanisms by which Kinesin and Dynein move myonuclei. The motors exert forces both directly on the nuclear surface and from the cell cortex via microtubules. How these activities are spatially segregated yet coordinated to position myonuclei is unknown. Using Drosophila melanogaster, we identified that Sunday Driver (Syd), a homolog of mammalian JNK-interacting protein 3 (JIP3), specifically regulates Kinesin- and Dynein-dependent cortical pulling of myonuclei without affecting motor activity near the nucleus. Specifically, Syd mediates Kinesin-dependent localization of Dynein to the muscle ends, where cortically anchored Dynein then pulls microtubules and the attached myonuclei into place. Proper localization of Dynein also requires activation of the JNK signaling cascade. Furthermore, Syd functions downstream of JNK signaling because without Syd, JNK signaling is insufficient to promote Kinesin-dependent localization of Dynein to the muscle ends. The significance of Syd-dependent myonuclear positioning is illustrated by muscle-specific depletion of Syd, which impairs muscle function. Moreover, both myonuclear spacing and locomotive defects in syd mutants can be rescued by expression of mammalian JIP3 in Drosophila muscle tissue, indicating an evolutionarily conserved role for JIP3 in myonuclear movement and highlighting the utility of Drosophila as a model for studying mammalian development. Collectively, we implicate Syd/JIP3 as a novel regulator of myogenesis that is required for proper intracellular organization and tissue function.
许多肌肉疾病的特征是肌细胞核定位错误，这突出了细胞内正确组织的重要性。肌细胞核的正确定位依赖于微管运动蛋白驱动蛋白-1和胞质动力蛋白，并且驱动蛋白和动力蛋白移动肌细胞核至少有两种不同的机制。这些马达蛋白既直接在核表面施加力，也通过微管从细胞皮质施加力。这些活动如何在空间上分离却又协调以定位肌细胞核尚不清楚。利用黑腹果蝇，我们发现周日驱动蛋白（Syd），即哺乳动物JNK相互作用蛋白3（JIP3）的同源物，特异性地调节依赖驱动蛋白和动力蛋白的肌细胞核皮质牵拉，而不影响细胞核附近的运动蛋白活性。具体而言，Syd介导动力蛋白依赖驱动蛋白定位于肌肉末端，在那里皮质锚定的动力蛋白随后将微管和附着的肌细胞核拉到合适位置。动力蛋白的正确定位还需要JNK信号级联的激活。此外，Syd在JNK信号下游发挥作用，因为没有Syd，JNK信号不足以促进动力蛋白依赖驱动蛋白定位于肌肉末端。Syd依赖的肌细胞核定位的重要性通过肌肉特异性缺失Syd得以体现，这会损害肌肉功能。此外，syd突变体中的肌细胞核间距和运动缺陷都可以通过在果蝇肌肉组织中表达哺乳动物JIP3来挽救，这表明JIP3在肌细胞核运动中具有进化保守的作用，并突出了果蝇作为研究哺乳动物发育模型的实用性。总之，我们认为Syd/JIP3是一种新的肌生成调节因子，是细胞内正确组织和组织功能所必需的。
