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ERK inhibition promotes neuroectodermal precursor commitment by blocking self-renewal and primitive streak formation of the epiblast.

ERK inhibition promotes neuroectodermal precursor commitment by blocking self-renewal and primitive streak formation of the epiblast.
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Yu Y, Wang X, Zhang X, Zhai Y, Lu X, Ma H, Zhu K, Zhao T, Jiao J, Zhao ZA, Li L,


Yu Y, Wang X, Zhang X, Zhai Y, Lu X, Ma H, Zhu K, Zhao T, Jiao J, Zhao ZA, Li L, (click to view)

Yu Y, Wang X, Zhang X, Zhai Y, Lu X, Ma H, Zhu K, Zhao T, Jiao J, Zhao ZA, Li L,

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Stem cell research & therapy 2018 01 059(1) 2 doi 10.1186/s13287-017-0750-8
Abstract
BACKGROUND
Pluripotent stem cells hold great promise for regenerative medicine. However, before clinical application, reproducible protocols for pluripotent stem cell differentiation should be established. Extracellular signal-regulated protein kinase (ERK) signaling plays a central role for the self-renewal of epiblast stem cells (EpiSCs), but its role for subsequent germ layer differentiation is still ambiguous. We proposed that ERK could modulate differentiation of the epiblast.

METHODS
PD0325901 was used to inhibit ERK activation during the differentiation of embryonic stem cells and EpiSCs. Immunofluorescence, western blot analysis, real-time PCR and flow cytometry were used to detect germ layer markers and pathway activation.

RESULTS
We demonstrate that the ERK phosphorylation level is lower in neuroectoderm of mouse E7.5 embryos than that in the primitive streak. ERK inhibition results in neural lineage commitment of epiblast. Mechanistically, PD0325901 abrogates the expression of primitive streak markers by β-catenin retention in the cytoplasm, and inhibits the expression of OCT4 and NANOG during EpiSC differentiation. Thus, EpiSCs differentiate into neuroectodermal lineage efficiently under PD0325901 treatment. These results suggest that neuroectoderm differentiation does not require extrinsic signals, supporting the default differentiation of neural lineage.

CONCLUSIONS
We report that a single ERK inhibitor, PD0325901, can specify epiblasts and EpiSCs into neural-like cells, providing an efficient strategy for neural differentiation.

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