A Genetic and Developmental Pathway from STAT3 to the OCT4-NANOG Circuit is Essential for Maintenance of ICM Lineages in vivo (Genes & Dev, June 2013)

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, STAT3-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived ESCs. We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the 4-cell, and later stage, embryos. Using Lif-null embryos we find STAT3 phosphorylation is dependent on LIF in 4-cell stage embryos. In blastocysts, IL-6 acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by 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 in pluripotent stem cells in vivo.



Dang Vinh Do1,2, Jun Ueda1, Daniel M. Messerschmidt3,Chanchao Lorthongpanich3, Yi Zhou2, Bo Feng5, Guoji Guo5, Peiyu J Lin2, Md Zakir Hossain1, Wenjun Zhang7, Akira Moh7, Qiang Wu2, Paul Robson5, Huck Hui Ng5, Lorenz Poellinger1,4, Barbara B. Knowles2,3,, Davor Solter3,6* and Xin-Yuan Fu1,2,7,8*

1 Cancer Science Institute of Singapore
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
3 Institute of Medical Biology, A*STAR, Singapore
4 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
5 Genome Institute of Singapore, A*STAR, Singapore
6 Duke NUS Graduate Medical School, Singapore
7 Life Sciences Institute, National University of Singapore, Singapore
8 Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA
*Co-corresponding Authors

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