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

Abstract

Trophoblast cells of the placenta are established at the blastocyst stage and differentiate into specialized subtypes after implantation. 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 and vasodilatory actions. The innermost layer, called the labyrinth, consists of branched villi that provide a large surface area for nutrient transport and are composed of trophoblast 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 that Gcm1, encoding the transcription factor glial cells missing-1 (Gcm1), is expressed in small clusters of chorionic trophoblast cells at the flat chorionic plate stage and at sites of chorioallantoic folding and extension when morphogenesis begins. Mutation of Gcm1 in mice causes a complete block to branching of the chorioallantoic interface, resulting in embryonic mortality by E10 due to the absence of the placental labyrinth. In addition, chorionic trophoblast cells in Gcm1-deficient placentas do not fuse to form syncytiotrophoblast. Abnormal development of placental villi is frequently associated with fetal death and intrauterine growth restriction in humans, and our studies provide the earliest molecular insight into this aspect of placental development.

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

“…Th e placental phenotypes of Bcl9l -defi cient mice were nearly identical to those reported for Gcm1 mutant mice 30,33 , which suggests that the mechanism underlying the placental defects in Bcl9l − / − concepti is due to the signifi cant reduction in Gcm1 expression. As Gcm1 is an upstream regulator of Synb 33 , these results suggest that BCL9L regulates ST-II fusion and diff erentiation by positively regulating the GCM1 / syncytin pathway.…”

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

“…Furthermore, it is possible that the post-translational modification of proteins other than Gcm1 contributes to the p45NF-E2-dependent placental phenotype. However, given the well-established pivotal role of Gcm1 in labyrinthine layer formation (Anson-Cartwright et al, 2000) and the current data showing that overexpression of Gcm1 is sufficient to increase syncytiotrophoblast formation, we conclude that enhanced expression of Gcm1 is crucial for the increased syncytiotrophoblast formation and the placental defect observed in p45NF-E2 -/-embryos.…”

“…Interestingly, both increased and decreased GCM1 expression have been reported in human placenta obtained from complicated pregnancies (Chen et al, 2004;Fujito et al, 2006;McCaig and Lyall, 2009). The placental defects associated with either the loss or gain of Gcm1 function observed in mice (Anson-Cartwright et al, 2000) (this paper) provide a rationale for the apparently paradoxical findings of the aforementioned clinical studies. The current results might aid in deciphering the mechanisms that result in placental dysfunction associated with low or high levels of GCM1 expression in humans.…”

“…It is required for (1) the initial folding of the chorion into simple branches and the subsequent branching morphogenesis within the placental labyrinthine layer and (2) syncytiotrophoblast fusion (Anson-Cartwright et al, 2000). Although, in the absence of Gcm1, both branching and syncytiotrophoblast fusion are impaired resulting in embryonic lethality at E10.5 (Anson-Cartwright et al, Schreiber et al, 2000a), overexpression of Gcm1 in p45NF-E2 -/-placenta has no apparent impact on EC or gross branching morphology.…”

“…Other bZip transcription factors, such as JunB, Fra1 (Fosl1), Tfeb (Tcfeb), Creb and Oasis (Creb3l1), regulate trophoblast differentiation or placental development (Schorpp-Kistner et al, 1999; Schreiber et al, 2000a;Schreiber et al, 2000b;Schubert et al, 2008;Steingrimsson et al, 1998). Creb and Oasis regulate the expression of Gcm1, a key regulator of placental development that is required for chorioallantoic branching and syncytiotrophoblast formation (Anson-Cartwright et al, 2000). The stability and binding activity of Gcm1 are furthermore posttranslationally regulated by acetylation.…”