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

Morikawa, Masato  ,  Koinuma, Daizo  ,  Mizutani, Anna  ,  Kawasaki, Natsumi  ,  Holmborn, Katarina  ,  Sundqvist, Anders  ,  Tsutsumi, Shuichi  ,  Watabe, Tetsuro  ,  Aburatani, Hiroyuki  ,  Heldin, Carl-Henrik  ,  Miyazono, Kohei

6 ( 1 )  , pp.64 - 73 , 2016-01-12 , Cell Press , Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University , Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo , Zebrafish Technology Platform, Science for Life Laboratory, Uppsala University , Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo , JST, PRESTO , Present address: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research , Present address: Department of Bio-matrix, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
UTokyo Research掲載「BMPがマウスES細胞の未分化性を維持する仕組み」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/the-roles-of-bmp-signaling-in-mouse-es-cells.html
UTokyo Research "The roles of BMP signaling in mouse ES cells" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/the-roles-of-bmp-signaling-in-mouse-es-cells.html
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 doubleknockout 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 Kru¨ppel-like factors.


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