Molecular mechanism of placental Development: The role of TMED2, a vesicular transport protein during labyrinth layer formation

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The placenta is the first organ formed in eutherian mammals and is essential for survival of the developing embryo. The mouse placenta, the model system that we study, is divided into three histologically distinct layers: decidual, spongiotrophoblast, and labyrinth. The labyrinth layer is the site of nutrient and gas exchange between the maternal and foetal environment. It consists of embryonic blood vessels that are in close proximity to maternal sinuses. In the mouse, labyrinth layer formation depends on attachment and fusion between two embryonic tissues: the chorion and the allantois. We showed that TMED2, a member of the emp24 domain family of cargo receptors, was expressed in the chorion and the allantois, and required for labyrinth layer formation. Thus, Tmed2 homozygous mutant embryos arrest at mid-gestation due to placental failure. To uncover the role of TMED2 in labyrinth layer development, we generated a chorioallantoic explant model and showed that it recapitulated the early molecular and morphological changes associated with labyrinth layer formation. Using this explant model, we found that TMED2 was required in the chorion for chorioallantoic attachment, and in both tissues for fusion and labyrinth layer formation. Importantly, we uncovered that TMED2 was required in the allantois for secretion of Fibronectin, an extracellular protein and potential cargo. Little is known about the function of TMED proteins during development and disease, although this family is conserved in all eukaryotes and essential for normal development. However, our work in the context of the placenta and the liver, combined with the work of others in multiple species and cell lines, indicates that TMED proteins are cargo receptors. Therefore, we will test two hypotheses: (1) TMED2-mediated transport of fibronectin is required in the allantois for chorioallantoic fusion; and (2) distinct TMED2-regulated pathways in the chorion and in the allantois are essential for labyrinth layer formation. The aims of this proposal are: (1) To determine if fibronectin is a TMED2 cargo protein and to uncover its role in labyrinth layer development; (2) To determine if TMED2 is required in both chorionic mesothelium and ectoderm for chorioallantoic attachment and fusion; and (3) To identify the TMED2-regulated pathways in the chorion and the allantois that are required for labyrinth layer formation. Our studies reveal a crucial role for TMED2 in placental development and, more specifically, in mediating communication between the chorion and allantois. Similar types of communication are essential for organogenesis. For example, during development of the lung where ventral foregut endodermal epithelium interacts with mesoderm to form the lungs. Since TMED2 and other members of this family are broadly expressed, we expect that our work will shed significant insight into the role of this protein and its cargoes in organogenesis.