ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Significance Defective placentation, including impaired uterine spiral artery remodeling, leads to pregnancy disorders such as pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth, all of which cause significant morbidity and mortality for the mother and fetus. Trophoblast cells are central to executing placental functions and can differentiate into two conserved specialized lineages: invasive/extravillous trophoblast cells, which guide uterine transformation, and syncytiotrophoblast, which serve a barrier function. We leveraged model systems to identify achaete-scute homolog 2 as a conserved regulator of the invasive/extravillous trophoblast cell lineage and a modulator of the syncytiotrophoblast phenotype. A key upstream regulator of trophoblast-engineered uterine transformation has been identified representing an entry point into the etiology of pregnancy complications resulting from defective placentation.