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ERK2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment.

TitleERK2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment.
Publication TypeJournal Article
Year of Publication2013
AuthorsHamilton WB, Kaji K, Kunath T
JournalPLoS One
Date Published2013
KeywordsAnimals, Cell Differentiation, Cells, Cultured, Embryonic Stem Cells, Genes, Immediate-Early, Mice, Mitogen-Activated Protein Kinase 1, Phosphorylation

Activation of the FGF-ERK pathway is necessary for naïve mouse embryonic stem (ES) cells to exit self-renewal and commit to early differentiated lineages. Here we show that genetic ablation of Erk2, the predominant ERK isozyme expressed in ES cells, results in hyper-phosphorylation of ERK1, but an overall decrease in total ERK activity as judged by substrate phosphorylation and immediate-early gene (IEG) induction. Normal induction of this subset of canonical ERK targets, as well as p90RSK phosphorylation, was rescued by transgenic expression of either ERK1 or ERK2 indicating a degree of functional redundancy. In contrast to previously published work, Erk2-null ES cells exhibited no detectable defect in lineage specification to any of the three germ layers when induced to differentiate in either embryoid bodies or in defined neural induction conditions. However, under self-renewing conditions Erk2-null ES cells express increased levels of the pluripotency-associated transcripts, Nanog and Tbx3, a decrease in Nanog-GFP heterogeneity, and exhibit enhanced self-renewal in colony forming assays. Transgenic add-back of ERK2 is capable of restoring normal pluripotent gene expression and self-renewal capacity. We show that ERK2 contributes to the destabilization of ES cell self-renewal by reducing expression of pluripotency genes, such as Nanog, but is not specifically required for the early stages of germ layer specification.

Alternate JournalPLoS ONE
PubMed ID23613754
PubMed Central IDPMC3628700
Grant ListF-0902 / / Parkinson's UK / United Kingdom
K-1205 / / Parkinson's UK / United Kingdom
MR/J012831/1 / / Medical Research Council / United Kingdom