Erk Signaling Is Indispensable For Genomic Stability And Self-renewal Of Mouse Embryonic Stem Cells

Inhibition of Mek/Erk signaling by pharmacological Mek inhibitor promotes selfrenewal and pluripotency of mouse embryonic stem cells(ESCs). Intriguingly, Erk signaling is essential for human ESC self-renewal. But the conflicting roles of Erk signaling in human and mouse ESCs might be due to species divergence. Human ESCs resemble mouse epiSCs in a primed pluripotency state, whereas mouse ESCs are maintained in a na?ve pluripotency state. To clarify the function of Erk1/2 in ESCs, endogenous Erk1 and Erk2 genes were disrupted in ESCs harboring an exogenous doxycycline(Dox)-inducible Erk1 gene, resulting in iErk1; Erk KO ESCs. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with mis-regulated expression of pluripotency genes, reduced cell proliferation, G1 cell cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes, but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal.Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability and self-renewal of ESCs...