title: BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden.
authors.forename: Masato
authors.initials: M
authors.lastname: Morikawa
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Mizutani
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: Zebrafish Technology Platform, Science for Life Laboratory, Uppsala University, 752 36 Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Holmborn
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; JST, PRESTO, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden. Electronic address: c-h.heldin@licr.uu.se.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: 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.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D000066673:Cell Self Renewal / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; C000715467:KLF4 protein, human; C498314:Klf2 protein, mouse; C000715468:Klf4 protein, mouse; C118391:Klf5 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051898:Smad1 Protein; D051902:Smad5 Protein