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

被引:55
作者
Morikawa, Masato [1 ]
Koinuma, Daizo [2 ]
Mizutani, Anna [2 ]
Kawasaki, Natsumi [2 ]
Holmborn, Katarina [3 ]
Sundqvist, Anders [1 ]
Tsutsumi, Shuichi [4 ]
Watabe, Tetsuro [2 ,5 ]
Aburatani, Hiroyuki [4 ]
Heldin, Carl-Henrik [1 ]
Miyazono, Kohei [1 ,2 ]
机构
[1] Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, S-75124 Uppsala, Sweden
[2] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan
[3] Uppsala Univ, Sci Life Lab, Zebrafish Technol Platform, S-75236 Uppsala, Sweden
[4] Univ Tokyo, Genome Sci Div, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan
[5] JST, PRESTO, Kawaguchi, Saitama 3320012, Japan
来源
STEM CELL REPORTS | 2016年 / 6卷 / 01期
基金
日本学术振兴会;
关键词
GROUND-STATE; MOUSE EMBRYO; HUMAN GENOME; PLURIPOTENCY; SPECIFICATION; BINDING;
D O I
10.1016/j.stemcr.2015.12.004
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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 Kruppel-like factors.
引用
收藏
页码:64 / 73
页数:10
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