Negative feedback via RSK modulates Erk-dependent progression from naive pluripotency

作者：Nett Isabelle R E; Mulas Carla; Gatto Laurent; Lilley Kathryn S; Smith Austin^*

来源：EMBO Reports, 2018, 19(8): UNSP e45642.

DOI：10.15252/embr.201745642

• embryonic stem cells
• mitogen-activated protein kinase
• pluripotency
• RSK
• signalling feedback

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 phospho-proteome 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 naive 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.

• 出版日期2018-8