Dll4 coordinates endothelial migration and smooth muscle cell recruitment to assemble the umbilical cord and placental vasculature

Proper development of the umbilical cord and placental vasculature is essential for embryonic growth and development. While the allantois is known give rise to endothelial cells within the placenta, whether the allantois gives rise to endothelial cells (ECs) in the umbilical cord is highly debated. Furthermore, a lack of genetic tools to study placental vascular development independent of the embryo proper has hindered robust investigation into the primary cause of vascular defects from early studies utilizing global knockouts. In this study, we sought to delineate the contribution of the allantois to the umbilical vessels and utilize a novel mouse genetic tool previously developed by our lab to revisit the role of Notch signaling during formation of the placental vasculature. We show that the allantois has mosaic contribution to the umbilical endothelium with higher contributions closer to the placenta. Loss of Notch signaling through deletion of Dll4 in the allantois causes abnormal vascular development in the umbilical cord and placenta with secondary defects on the heart. Lastly, we identify Unc5b as a novel effector of Dll4 signaling that simultaneously restricts EC migration while promoting chemokine signaling for vascular smooth muscle cell recruitment to arteries. These findings identify a novel genetic tool for investigating placental vascular development and give new insights into the ontogeny and mechanisms of placental and umbilical vascular development.