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

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2016 Jan 16

PMID 26771354

Citations 41

Authors

Masato Morikawa

Daizo Koinuma

Anna Mizutani

Natsumi Kawasaki

Katarina Holmborn

Anders Sundqvist

Shuichi Tsutsumi

Tetsuro Watabe

Hiroyuki Aburatani

Carl-Henrik Heldin

Kohei Miyazono

Affiliations

Soon will be listed here.

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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