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Receptor tyrosine kinase signaling pathways are key regulators for the formation of the primitive endoderm (PrE) and the epiblast (Epi) from the inner cell mass (ICM) of the mouse preimplantation embryo. Among them, FGF signaling is critical for PrE cell specification, whereas PDGF signaling is critical for the survival of committed PrE cells. Here, we investigated possible functional redundancies among FGF, PDGF, and KIT signaling and showed that only PDGF signaling is involved in PrE cell survival. In addition, we analyzed the effectors downstream of PDGFRα. Our results suggest that the role of PDGF signaling in PrE cell survival is mediated through PI3K‐mTOR and independently from p53. Lastly, we uncovered a role for PI3K‐mTOR signaling in the survival of Epi cells. Taken together, we propose that survival of ICM cell lineages relies on the regulation of PI3K‐mTOR signaling through the regulation of multiple signaling pathways.  Stem Cells   2019;37:888–898

PDGF Signaling in Primitive Endoderm Cell Survival Is Mediated by PI3K‐mTOR Through p53‐Independent Mechanism