Insulin receptor substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface

The placental labyrinth is the primary site of maternal-fetal exchange, and its disruption contributes to placental insufficiency and fetal growth restriction (FGR). Here, we identify insulin receptor substrate 2 (IRS2) as a key regulator of mouse placental labyrinth development. Irs2 is expressed in the syncytiotrophoblast (SynT) layers of the labyrinth, where it integrates growth factor signaling during placental morphogenesis. Loss of IRS2 disrupts labyrinth organization, causing defective SynT-II differentiation, impaired trophoblast fusion, and reduced fetal vascularization. Using CRISPR-Cas9-engineered Irs2^-/- trophoblast stem cells, we show that IRS2 deficiency impairs upregulation of the SynT-II regulators Pparγ and Gcm1, disrupting SynT-II differentiation and sinusoidal trophoblast giant cell specification. Mechanistically, IRS2 relays insulin-like growth factor (IGF) signals through phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways to coordinate trophoblast proliferation, differentiation, and vascular morphogenesis. Human trophoblast stem cell differentiation and organoid analyses reveal IRS2 enrichment in the human syncytiotrophoblast (STB), indicating conserved expression at the human maternal-fetal interface.