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Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos


In blastocyst chimeras, embryonic stem (ES) cells contribute to embryonic tissues but not extraembryonic trophectoderm. Conditional activation of HRas1Q61L in ES cells in vitro induces the trophectoderm marker Cdx2 and enables derivation of trophoblast stem (TS) cell lines that, when injected into blastocysts, chimerize placental tissues. Erk2, the downstream effector of Ras–mitogen-activated protein kinase (MAPK) signaling, is asymmetrically expressed in the apical membranes of the 8-cell-stage embryo just before morula compaction. Inhibition of MAPK signaling in cultured mouse embryos compromises Cdx2 expression, delays blastocyst development and reduces trophectoderm outgrowth from embryo explants. These data show that ectopic Ras activation can divert ES cells toward extraembryonic trophoblastic fates and implicate Ras-MAPK signaling in promoting trophectoderm formation from mouse embryos.

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Figure 1: Induction of activated Ras expression promotes formation of trophoblastic tumors from ES cells.
Figure 2: Trophoblastic stem cell establishment from iRasES cells.
Figure 3: Expression of Cdx2, Nanog and Oct4 in response to Ras-MAPK signaling in ES cells.
Figure 4: Ras-MAPK signaling regulates Cdx2 expression and trophoblast outgrowth in mouse embryos.


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This study was supported by grants from the US National Institutes of Health and the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research. G.Q.D. is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. We are grateful to J. Rossant (Hospital for Sick Children, University of Toronto, Canada) for providing TS cells and experimental advice and for critical reading of this manuscript.

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Authors and Affiliations



C.-W.L. designed and executed experiments and wrote the manuscript. A.Y., L.C., S.V. and K.K. executed experiments, contributed reagents, and edited the manuscript. G.Q.D. designed the experiments and wrote the manuscript.

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Correspondence to George Q Daley.

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Lu, CW., Yabuuchi, A., Chen, L. et al. Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nat Genet 40, 921–926 (2008).

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