A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo
A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo
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DOI：
10.1101/gad.221176.113
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发表时间：
2013-06-15
影响因子：
10.5
通讯作者：
Fu, Xin-Yuan
中科院分区：
文献类型：
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作者：
Dang Vinh Do;Ueda, Jun;Fu, Xin-Yuan
尽管已知 OCT4-NANOG 是体外维持多能细胞所必需的，但在体内早期发育过程中调节该电路的上游信号尚未确定。在这里，我们首次证明了 OCT4-NANOG 电路的信号转导器和转录激活剂 3 (STAT3) 依赖性调节是维持多能内细胞团 (ICM) 所必需的，ICM 是体外衍生的胚胎干细胞 (ESC) 的来源。我们发现 STAT3 在小鼠卵母细胞中高度表达，并在四细胞和后期胚胎中磷酸化并易位至细胞核。使用白血病抑制因子 (Lif) 缺失的胚胎，我们发现四细胞阶段胚胎中 STAT3 磷酸化依赖于 LIF。在囊胚中，白细胞介素 6 (IL-6) 以自分泌方式发挥作用，确保 STAT3 磷酸化，由 janus 激酶 1 (JAK1)（一种 LIF 和 IL-6 依赖性激酶）介导。使用基因工程小鼠品系消除卵母细胞和胚胎中的 Stat3，我们确信 STAT3 对于 ICM 谱系的维持至关重要，但对于 ICM 和滋养外胚层的形成却不是必需的。事实上，STAT3 直接与 Oct4 和 Nanog 远端增强子结合，调节它们的表达以维持小鼠胚胎和诱导多能干细胞的多能性。这些结果提供了一种通过植入前胚胎和体内多能干细胞中的 STAT3 来决定细胞命运的新遗传模型。
Although it is known that OCT4-NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.