A genetic and developmental pathway from STAT3 to the OCT4–NANOG circuit is essential for maintenance of ICM lineages in vivo
- Dang Vinh Do1,2,
- Jun Ueda1,
- Daniel M. Messerschmidt3,
- Chanchao Lorthongpanich3,
- Yi Zhou2,
- Bo Feng4,
- Guoji Guo4,
- Peiyu J. Lin2,
- Md Zakir Hossain1,
- Wenjun Zhang5,
- Akira Moh5,
- Qiang Wu2,
- Paul Robson4,
- Huck Hui Ng4,
- Lorenz Poellinger1,6,
- Barbara B. Knowles2,3,
- Davor Solter3,7,9 and
- Xin-Yuan Fu1,2,5,8,9
- 1Cancer Science Institute of Singapore, Singapore 117599, Singapore;
- 2Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119615, Singapore;
- 3Institute of Medical Biology, A*STAR, Singapore 138648, Singapore;
- 4Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore;
- 5Life Sciences Institute, National University of Singapore, Singapore 119615, Singapore;
- 6Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-17177, Sweden;
- 7Duke NUS Graduate Medical School, Singapore 169857, Singapore, Singapore;
- 8Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
Abstract
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.
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Footnotes
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↵9 Corresponding authors
E-mail davor.solter{at}imb.a-star.edu.sg
E-mail xin-yuan_fu{at}nuhs.edu.sg
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.221176.113.
- Received November 30, 2012.
- Accepted May 20, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press