Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells
Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells
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DOI：
10.1073/pnas.0609100104
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发表时间：
2007-03-06
影响因子：
11.1
通讯作者：
Schneider, Michael D.
中科院分区：
文献类型：
--
作者：
Liu, Yu;Asakura, Masanori;Schneider, Michael D.
心脏特化的早期步骤对于哺乳动物胚胎的研究来说是有问题的，哺乳动物胚胎倾向于使用重现心肌生成的多能细胞。此外，控制心脏规格的回路与 ES 细胞和其他细胞在心脏修复中的应用相关。在小鼠畸胎癌细胞中，抑制鸟类或两栖动物胚胎和外植体心脏形成的典型 Wnt 却相反地激活了心脏发生。在这里，我们表明 Wnt/β-连环蛋白途径对于 ES 细胞中发生的心肌生成也是至关重要的，在原肠胚形成样阶段发挥作用，介导中胚层形成和模式形成（心肌生成本身的两个先决条件）。与此步骤暂时相关的基因包括 Sox17，它编码吸热 HMG-box 转录因子。使用慢病毒载体进行 RNA 干扰来分化 ES 细胞，证明了 Sox17 在心肌细胞形成中的重要作用。 Sox17 短发夹 RNA 选择性抑制心肌生成，在中胚层形成之后、Mesp1 和 Mesp2 诱导之前发挥作用，Mesp1 和 Mesp2 是一对相关的基本螺旋-环-螺旋转录因子，它们共同对于形成心脏中胚层是必不可少的。 Sox17 短发夹 RNA 可非细胞自主地阻断心肌生成，并损害 Hex 的诱导，Hex 是一种同源域转录因子，已知是产生内胚层衍生的心脏诱导因子所需的。
Early steps for cardiac specification are problematic for the study of mammalian embryos, which has favored using pluripotent cells that recapitulate cardiac myogenesis. Furthermore, circuits governing cardiac specification have relevance to the application of ES cells and other cells for heart repair. In mouse teratocarcinoma cells, canonical Wnts that inhibit heart formation in avian or amphibian embryos and explants activate cardiogenesis, paradoxically. Here, we show that the Wnt/beta-catenin pathway also is essential for cardiac myogenesis to occur in ES cells, acting at a gastrulation-like stage, mediating mesoderm formation and patterning (two prerequisites for cardiac myogenesis itself). Among genes associated temporally with this step was Sox17, encoding an endothermal HMG-box transcription factor. Using lentiviral vectors for RNA interference in differentiating ES cells, an essential role for Sox17 was proven in cardiac muscle cell formation. Sox17 short-hairpin RNA suppresses cardiac myogenesis selectively, acting subsequent to mesoderm formation yet before induction of Mesp1 and Mesp2, a pair of related basic helix-loop-helix transcription factors that together are indispensable for creating heart mesoderm. Sox17 short-hairpin RNA blocks cardiac myogenesis non-cell autonomously and impairs the induction of Hex, a homeodomain transcription factor that is known to be required for the production of endoderm-derived heart-inducing factors.