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Significance Reproductive success in placental mammals relies on proper development of the trophoblast lineage. In particular, a proper balance in self-renewal vs. differentiation of trophoblast progenitors is critical for establishment of pregnancy. A defect in this process causes early pregnancy loss. Here, we showed that the Hippo signaling effector, TEAD4, is essential for trophoblast progenitor self-renewal in early postimplantation mammalian embryos. Using genetic mouse models and human TSCs, including TSCs from patients with recurrent pregnancy losses, we identified a TEAD4-dependent, evolutionarily conserved gene expression program that promotes stemness and cell proliferation in trophoblast progenitors and ensures in utero survival of the developing fetus.

TEAD4 ensures postimplantation development by promoting trophoblast self-renewal: An implication in early human pregnancy loss