Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E8996-E9005. doi: 10.1073/pnas.1708725114. Epub 2017 Oct 9.
Tissue regeneration depends on the timely activation of adult stem cells. In skeletal muscle, the adult stem cells maintain a quiescent state and proliferate upon injury. We show that muscle stem cells (MuSCs) use direct translational repression to maintain the quiescent state. High-resolution single-molecule and single-cell analyses demonstrate that quiescent MuSCs express high levels of Myogenic Differentiation 1 (MyoD) transcript in vivo, whereas MyoD protein is absent. RNA pulldowns and costainings show that MyoD mRNA interacts with Staufen1, a potent regulator of mRNA localization, translation, and stability. Staufen1 prevents MyoD translation through its interaction with the MyoD 3'-UTR. MuSCs from Staufen1 heterozygous (Staufen1) mice have increased MyoD protein expression, exit quiescence, and begin proliferating. Conversely, blocking MyoD translation maintains the quiescent phenotype. Collectively, our data show that MuSCs express MyoD mRNA and actively repress its translation to remain quiescent yet primed for activation.
组织再生依赖于成体干细胞的适时激活。在骨骼肌中，成体干细胞处于静止状态，并在损伤后增殖。我们发现肌肉干细胞（MuSCs）利用直接翻译抑制来维持静止状态。高分辨率单分子和单细胞分析表明，体内静止的 MuSCs 表达高水平的肌生成分化 1（MyoD）转录本，而 MyoD 蛋白不存在。RNA 下拉和共染色显示，MyoD mRNA 与 Staufen1 相互作用，Staufen1 是一种强大的 mRNA 定位、翻译和稳定性的调节剂。Staufen1 通过与 MyoD 3'-UTR 的相互作用阻止 MyoD 翻译。Staufen1 杂合（Staufen1）小鼠的 MuSCs 表达更多的 MyoD 蛋白，退出静止状态并开始增殖。相反，阻止 MyoD 翻译可维持静止表型。总的来说，我们的数据表明 MuSCs 表达 MyoD mRNA，并积极抑制其翻译以保持静止但为激活做好准备。
