IBENS, Institut de Biologie de l'Ecole Normale Supérieure, 75005 Paris, France; INSERM U1024, 75005 Paris, France; CNRS UMR 8197, 75005 Paris, France.
IBENS, Institut de Biologie de l'Ecole Normale Supérieure, 75005 Paris, France; INSERM U1024, 75005 Paris, France; CNRS UMR 8197, 75005 Paris, France.
Dev Cell. 2017 Sep 11;42(5):527-541.e4. doi: 10.1016/j.devcel.2017.08.004. Epub 2017 Aug 31.
Skeletal muscle contraction is mediated by myofibrils, complex multi-molecular scaffolds structured into repeated units, the sarcomeres. Myofibril structure and function have been extensively studied, but the molecular processes regulating its formation within the differentiating muscle cell remain largely unknown. Here we show in zebrafish that genetic interference with the Quaking RNA-binding proteins disrupts the initial steps of myofibril assembly without affecting early muscle differentiation. Using RNA sequencing, we demonstrate that Quaking is required for accumulation of the muscle-specific tropomyosin-3 transcript, tpm3.12. Further functional analyses reveal that Tpm3.12 mediates Quaking control of myofibril formation. Moreover, we identified a Quaking-binding site in the 3' UTR of tpm3.12 transcript, which is required in vivo for tpm3.12 accumulation and myofibril formation. Our work uncovers a Quaking/Tpm3 pathway controlling de novo myofibril assembly. This unexpected developmental role for Tpm3 could be at the origin of muscle defects observed in human congenital myopathies associated with tpm3 mutation.
骨骼肌收缩是由肌原纤维介导的，肌原纤维是一种复杂的多分子支架，构成重复的单位，即肌节。肌原纤维的结构和功能已经得到了广泛的研究，但调节其在分化的肌肉细胞中形成的分子过程在很大程度上仍然未知。在这里，我们在斑马鱼中表明，与 Quaking RNA 结合蛋白的遗传干扰会破坏肌原纤维组装的初始步骤，而不影响早期肌肉分化。通过 RNA 测序，我们证明 Quaking 是积累肌肉特异性原肌球蛋白-3 转录本 tpm3.12 所必需的。进一步的功能分析表明，Tpm3.12 介导了 Quaking 对肌原纤维形成的控制。此外，我们在 tpm3.12 转录本的 3'UTR 中鉴定出一个 Quaking 结合位点，该位点在体内对于 tpm3.12 的积累和肌原纤维的形成是必需的。我们的工作揭示了一种 Quaking/Tpm3 通路，它可以控制新的肌原纤维组装。这种 Tpm3 在发育过程中的意想不到的作用可能是与 tpm3 突变相关的人类先天性肌病中观察到的肌肉缺陷的起源。
