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A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells

Nature volume 460, pages 118–122 (2009)Cite this article

Abstract

The cytokine leukaemia inhibitory factor (LIF) integrates signals into mouse embryonic stem (ES) cells to maintain pluripotency. Although the Jak–Stat3 pathway is essential and sufficient to mediate LIF signals1,2, it is still unclear how these signals are linked to the core circuitry of pluripotency-associated transcription factors, consisting of Oct3/4 (also called Pou5f1), Sox2 and Nanog3,4. Here we show that two LIF signalling pathways are each connected to the core circuitry via different transcription factors. In mouse ES cells, Klf4 is mainly activated by the Jak–Stat3 pathway and preferentially activates Sox2, whereas Tbx3 is preferentially regulated by the phosphatidylinositol-3-OH kinase–Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog. In the absence of LIF, artificial expression of Klf4 or Tbx3 is sufficient to maintain pluripotency while maintaining the expression of Oct3/4. Notably, overexpression of Nanog supports LIF-independent self-renewal of mouse ES cells in the absence of Klf4 and Tbx3 activity. Therefore, Klf4 and Tbx3 are involved in mediating LIF signalling to the core circuitry but are not directly associated with the maintenance of pluripotency, because ES cells keep pluripotency without their expression in the particular context.

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Figure 1: Tbx3 and Klf4 support LIF-independent self-renewal of mouse ES cells.
Figure 2: Expression of pluripotency-associated transcription factors in LIF-independent ES cell lines.
Figure 3: Pathway-specific effects of LIF signals on the expression of Tbx3 and Klf4.
Figure 4: Diagram of the parallel circuitry of the LIF signal pathways integrating into the transcription factor network.

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Acknowledgements

We thank T. Nakano for providing the AktER expressing ES cells.

Author Contributions H.N. conceived the study; H.N. and K.O. designed and executed experiments; D.S. performed embryo manipulation; K.A. contributed experimental advice; and H.N. interpreted experiments and wrote the paper.

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Authors and Affiliations

  1. Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan ,

    Hitoshi Niwa, Kazuya Ogawa, Daisuke Shimosato & Kenjiro Adachi

  2. Laboratory for Development and Regenerative Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuo-ku, Kobe 6500017, Japan ,

    Hitoshi Niwa & Daisuke Shimosato

  3. JST, CREST, Sanbancho, Chiyoda-ku, Tokyo, 1020075, Japan ,

    Hitoshi Niwa

Authors
  1. Hitoshi Niwa
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  2. Kazuya Ogawa
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  4. Kenjiro Adachi
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Corresponding author

Correspondence to Hitoshi Niwa.

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Niwa, H., Ogawa, K., Shimosato, D. et al. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460, 118–122 (2009). https://doi.org/10.1038/nature08113

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