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

86 Citations (Scopus)

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

Fingerprint

STAT3 Transcription Factor
Cell Lineage
Maintenance
Embryonic Structures
Blastocyst
Oocytes
Interleukin-6
Janus Kinase 1
Phosphorylation
Leukemia Inhibitory Factor
Induced Pluripotent Stem Cells
Pluripotent Stem Cells
Genetic Models
Embryonic Stem Cells
Phosphotransferases

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Do, D. V., Ueda, J., Messerschmidt, D. M., Lorthongpanich, C., Zhou, Y., Feng, B., ... 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

A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. / Do, Dang Vinh; 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.

In: Genes and Development, Vol. 27, No. 12, 15.06.2013, p. 1378-1390.

Research output: Contribution to journalArticle

Do, DV, Ueda, J, Messerschmidt, DM, Lorthongpanich, C, Zhou, Y, Feng, B, Guo, G, Lin, PJ, Hossain, MZ, Zhang, W, Moh, A, Wu, Q, Robson, P, Ng, HH, Poellinger, L, Knowles, BB, Solter, D & Fu, XY 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, vol. 27, no. 12, pp. 1378-1390. https://doi.org/10.1101/gad.221176.113
Do, Dang Vinh ; 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. / A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. In: Genes and Development. 2013 ; Vol. 27, No. 12. pp. 1378-1390.
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AU - Do, Dang Vinh

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AU - Lorthongpanich, Chanchao

AU - Zhou, Yi

AU - Feng, Bo

AU - Guo, Guoji

AU - Lin, Peiyu J.

AU - Hossain, Md Zakir

AU - Zhang, Wenjun

AU - Moh, Akira

AU - Wu, Qiang

AU - Robson, Paul

AU - Ng, Huck Hui

AU - Poellinger, Lorenz

AU - Knowles, Barbara B.

AU - Solter, Davor

AU - Fu, Xin Yuan

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N2 - 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.

AB - 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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