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Stem Cell Reports. 2016 Jan 12;6(1):64-73. doi: 10.1016/j.stemcr.2015.12.004.

BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.

Author information

1
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden.
2
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
3
Zebrafish Technology Platform, Science for Life Laboratory, Uppsala University, 752 36 Uppsala, Sweden.
4
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
5
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; JST, PRESTO, Kawaguchi, Saitama 332-0012, Japan.
6
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden. Electronic address: c-h.heldin@licr.uu.se.
7
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: miyazono@m.u-tokyo.ac.jp.

Abstract

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors.

PMID:
26771354
PMCID:
PMC4719190
DOI:
10.1016/j.stemcr.2015.12.004
[Indexed for MEDLINE]
Free PMC Article

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