@article{37c79957b2a04f5b89d3702e5c02a618,
title = "Negative feedback via RSK modulates Erk-dependent progression from na{\"i}ve pluripotency",
abstract = "Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling is implicated in initiation of embryonic stem (ES) cell differentiation. The pathway is subject to complex feedback regulation. Here, we examined the ERK-responsive phosphoproteome in ES cells and identified the negative regulator RSK1 as a prominent target. We used CRISPR/Cas9 to create combinatorial mutations in RSK family genes. Genotypes that included homozygous null mutations in Rps6ka1, encoding RSK1, resulted in elevated ERK phosphorylation. These RSK-depleted ES cells exhibit altered kinetics of transition into differentiation, with accelerated downregulation of na{\"i}ve pluripotency factors, precocious expression of transitional epiblast markers and early onset of lineage specification. We further show that chemical inhibition of RSK increases ERK phosphorylation and expedites ES cell transition without compromising multilineage potential. These findings demonstrate that the ERK activation profile influences the dynamics of pluripotency progression and highlight the role of signalling feedback in temporal control of cell state transitions.",
keywords = "embryonic stem cells, mitogen-activated protein kinase, pluripotency, RSK, signalling feedback",
author = "Nett, {Isabelle R.E.} and Carla Mulas and Laurent Gatto and Lilley, {Kathryn S.} and Austin Smith",
note = "Funding Information: We are grateful to Jason Wray and Tu}zer Kalkan for advice. We thank Andy Riddell for flow cytometry support and Mike Deery for mass spectrometry support. We also thank Rosalind Drummond for valuable technical assistance and Martin Leeb and J{\"o}rg Betschinger for helpful discussions. This research was funded by European Commission Projects EuroSyStem (HEALTH-F4-2008-200720) and SyBoss (242129) and the Leverhulme Trust (RPG-2016-418). The Cambridge Stem Cell Institute receives core funding from The Wellcome Trust and The Medical Research Council. AS is a Medical Research Council Professor. Funding Information: We are grateful to Jason Wray and T{\H u}zer Kalkan for advice. We thank Andy Riddell for flow cytometry support and Mike Deery for mass spectrometry support. We also thank Rosalind Drummond for valuable technical assistance and Martin Leeb and J{\"o}rg Betschinger for helpful discussions. This research was funded by European Commission Projects EuroSyStem (HEALTH-F4-2008-200720) and SyBoss (242129) and the Leverhulme Trust (RPG-2016-418). The Cambridge Stem Cell Institute receives core funding from The Wellcome Trust and The Medical Research Council. AS is a Medical Research Council Professor. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2018",
month = aug,
doi = "10.15252/embr.201745642",
language = "English",
volume = "19",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Wiley-Blackwell",
number = "8",
}
