Insulin Receptor Substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface

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 signalling 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 PI3K/AKT and MAPK pathways to coordinate trophoblast proliferation, differentiation and vascular morphogenesis.