The glial cells missing-1 protein is essential for branching morphogenesisin the chorioallantoic placenta

Trophoblast cells of the placenta are established at the blastocyst stage a nd differentiate into specialized subtypes after implantation(1,2). In mice , the outer layer of the placenta consists of trophoblast giant cells that invade the uterus and promote maternal blood flow to the implantation site by producing cytokines with angiogenic(3) and vasodilatory(4) actions. The innermost layer, called the labyrinth, consists of branched villi that prov ide a large surface area for nutrient transport and are composed of trophob last cells and underlying mesodermal cells derived from the allantois. The chorioallantoic villi develop after embryonic day (E) 8.5 through extensive folding and branching of an initially flat sheet of trophoblast cells, the chorionic plate, in response to contact with the allantois. We show here t hat Gcm1. encoding the transcription factor glial cells missing-1 (Gcm1). i s expressed in small clusters of chorionic trophoblast cells at the flat ch orionic plate stage and at sites of chorioallantoic folding and extension w hen morphogenesis begins. Mutation of Gcm1 in mice causes a complete block to branching of the chorioallantoic interface, resulting in embryonic morta lity by E10 due to the absence of the placental labyrinth. In addition, cho rionic trophoblast cells in Gcm1-deficient placentas do not fuse to form sy ncytiotrophoblast. Abnormal development of placental villi is frequently as sociated with fetal death and intrauterine growth restriction in humans, an d our studies provide the earliest molecular insight into this aspect of pl acental development.