Control of fluid flow by Adgrd1 is essential for mammalian oviductal embryo transport

Dysfunction of oviductal embryo transport can lead to ectopic pregnancy which affects 1 to 2% of all conceptions in the United States and Europe, and is the most common cause of pregnancy-related death in the first trimester1, 2. Ectopic pregnancies almost always occur in the Fallopian tube, emphasizing the critical role of oviductal transport in human reproduction3. Oviductal transit is regulated and involves a valve-like "tubal-locking" phenomenon that temporarily arrests oocytes at the ampullary-isthmic junction (AIJ) where fertilization occurs4. Here, we show that female mice lacking the orphan adhesion G-protein coupled receptor Adgrd1 are sterile because they are unable to unlock the restraining mechanism at the AIJ, inappropriately retaining embryos within the oviduct. Adgrd1 is expressed on the oviductal epithelium and the post-ovulatory attenuation of tubal fluid production is dysregulated in Adgrd1-deficient mice. We identified Plxdc2 as an activating ligand for Adgrd1 displayed on the surface of cumulus cells. Our findings suggest that regulating oviductal luminal fluid production by Adgrd1 controls embryo transit, and provides important insights into the genetic regulation and molecular mechanisms involved embryo tubal transport.