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

Stem Cell Reports
Masato MorikawaKohei Miyazono

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.

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Citations

Aug 9, 2016·Cell Reports·Charles A C WilliamsGreg M Findlay
Nov 1, 2016·Glycoconjugate Journal·Shoko Nishihara
Dec 1, 2017·Nucleic Acids Research·Anders SundqvistPeter Ten Dijke
Sep 1, 2017·Genes, Chromosomes & Cancer·M Ampuja, Anne Kallioniemi
Sep 15, 2016·Oncotarget·Chevaun D MorrisonWilliam P Schiemann
Jun 15, 2017·BMC Developmental Biology·Sophie MorganiAnna-Katerina Hadjantonakis
Feb 12, 2017·Clinical Science·Christina A EichstaedtEkkehard Grünig
Mar 7, 2020·Frontiers in Cell and Developmental Biology·Majid Mossahebi-MohammadiXiaokun Li
May 26, 2017·Stem Cells and Development·Ludovic ZimmerlinElias T Zambidis
Apr 4, 2019·Life Science Alliance·Hiroko MorimotoTakashi Shinohara
Sep 30, 2016·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Xinjun ChenDanping Liu
Jan 30, 2021·Computational and Structural Biotechnology Journal·Lidia RuizMaria J Macias
Mar 25, 2021·Developmental Biology·Joshua W VincentzAnthony B Firulli
May 4, 2021·Frontiers in Cell and Developmental Biology·Makoto NasuKenji Shimamura
Aug 9, 2017·ACS Chemical Biology·Jamie R GentheMartine F Roussel

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Methods Mentioned

BETA
immunoprecipitation
ChIP-seq
ChIP
transgenic

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