A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo

作者：Dang Vinh Do; Ueda Jun; Messerschmidt Daniel M; Lorthongpanich Chanchao; Zhou Yi; Feng Bo; Guo Guoji; Lin Peiyu J; Hossain Md Zakir; Zhang Wenjun; Moh Akira; Wu Qiang; Robson Paul; Ng Huck Hui; Poellinger Lorenz; Knowles Barbara B; Solter Davor^*; Fu Xin Yuan

来源：Genes & Development, 2013, 27(12): 1378-1390.

DOI：10.1101/gad.221176.113

• embryogenesis
• inner cell mass
• STAT3
• OCT4
• NANOG
• embryonic stem cell

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.

• 出版日期2013-6-15
• 单位河北医科大学