Premium
Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency
Author(s) -
Nett Isabelle RE,
Mulas Carla,
Gatto Laurent,
Lilley Kathryn S,
Smith Austin
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745642
Subject(s) - mapk/erk pathway , microbiology and biotechnology , epiblast , phosphorylation , biology , cell fate determination , embryonic stem cell , kinase , protein kinase a , regulator , cellular differentiation , signal transduction , genetics , transcription factor , embryogenesis , gene , embryo , gastrulation
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 RSK 1 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 RSK 1, 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.