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Updated: Feb 9, 2026
09:07
Chemical Reversion of Conventional Human Pluripotent Stem Cells to a Naïve-like State with Improved Multilineage Differentiation Potency
Published on: June 10, 2018
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Negative feedback via RSK modulates Erk-dependent progression from naïve pluripotency
Isabelle Re Nett1, Carla Mulas1, Laurent Gatto2,3
1Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
EMBO Reports
|June 14, 2018
Summary
Ribosomal S6 kinase 1 (RSK1) negatively regulates mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in embryonic stem cells. RSK1 depletion accelerates cell differentiation by altering ERK phosphorylation dynamics.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Signaling
Background:
- Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways are crucial for embryonic stem (ES) cell differentiation.
- These signaling pathways are subject to intricate feedback mechanisms that control their activity.
- Understanding these feedback loops is essential for deciphering the temporal control of cell state transitions.
Purpose of the Study:
- To investigate the ERK-responsive phosphoproteome in ES cells.
- To identify key regulators of ERK signaling involved in ES cell differentiation.
- To elucidate the role of RSK family kinases in feedback regulation of ERK signaling.
Main Methods:
- Utilized CRISPR/Cas9 gene editing to generate combinatorial mutations in RSK family genes.
- Analyzed ERK phosphorylation levels in RSK-depleted ES cells.
- Assessed the kinetics of ES cell differentiation, including pluripotency factor downregulation and epiblast marker expression.
- Investigated the effects of chemical RSK inhibition on ERK phosphorylation and ES cell differentiation.
Main Results:
- Identified RSK1 as a prominent negative regulator within the ERK-responsive phosphoproteome.
- Homozygous null mutations in Rps6ka1 (encoding RSK1) led to elevated ERK phosphorylation.
- RSK-depleted ES cells showed accelerated differentiation kinetics, including faster pluripotency factor downregulation and earlier lineage specification.
- Chemical inhibition of RSK expedited ES cell transition and increased ERK phosphorylation without impairing multilineage potential.
Conclusions:
- The ERK activation profile critically influences the dynamics of pluripotency progression in ES cells.
- Signaling feedback mechanisms, particularly involving RSK, play a vital role in the temporal control of cell state transitions.
- RSK1 acts as a key negative regulator, fine-tuning ERK signaling to modulate the timing of ES cell differentiation.
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