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

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

Research output: Contribution to journalArticle

96 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1378-1390
Number of pages13
JournalGenes and Development
Volume27
Issue number12
DOIs
StatePublished - Jun 15 2013

Keywords

  • Embryogenesis
  • Embryonic stem cell
  • Inner cell mass
  • NANOG
  • OCT4
  • STAT3

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Do, D. V., Ueda, J., Messerschmidt, D. M., Lorthongpanich, C., Zhou, Y., Feng, B., Guo, G., Lin, P. J., Hossain, M. Z., Zhang, W., Moh, A., Wu, Q., Robson, P., Ng, H. H., Poellinger, L., Knowles, B. B., Solter, D., & Fu, X. Y. (2013). A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes and Development, 27(12), 1378-1390. https://doi.org/10.1101/gad.221176.113