Negative feedback via RSK modulates Erk-dependent progression from naïve pluripotency.
Isabelle Re NettCarla MulasLaurent GattoKathryn S LilleyAustin G SmithPublished in: EMBO reports (2018)
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 naïve 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.
Keyphrases
- signaling pathway
- induced apoptosis
- pi k akt
- cell proliferation
- cell cycle arrest
- early onset
- crispr cas
- single cell
- cell fate
- protein kinase
- poor prognosis
- late onset
- cell therapy
- oxidative stress
- embryonic stem cells
- genome editing
- genome wide
- endoplasmic reticulum stress
- mesenchymal stem cells
- risk assessment
- long non coding rna
- binding protein
- tyrosine kinase
- climate change