Off to a good start: The importance of the placental exchange surface - Lessons from the mouse.

The role of the chorio-allantoic placenta as the critical nutrient- and oxygen-supplying organ to nourish the demands of the fetus has been well recognized. This function relies on the successful establishment of the placental feto-maternal exchange unit, or interhaemal barrier, across which all nutrients as well as waste products must pass to cross from the maternal to the fetal blood circulation, or vice versa, respectively. As a consequence, defects in the establishment of this elaborate interface lead to fetal growth retardation or even embryonic lethality, depending on the severity of the defect. Beyond this essential role, however, it has also emerged that the functionality of the feto-maternal interface dictates the proper development of specific embryonic organs, with tightest links observed to the formation of the heart. In this article, we build on the foundational strength of the mouse as experimental model in which the placental causality of embryonic defects can be genetically proven. We discuss in detail the formation of the interhaemal barrier that makes up the labyrinth layer of the murine placenta, including insights into drivers of its formation and the interdependence of the cell types that make up this essential interface, from in vivo and in vitro data using mouse trophoblast stem cells. We highlight mouse genetic tools that enable the elucidation of cause-effect relationships between defects driven by either the trophoblast cells of the placenta or by embryonic cell types. We specifically emphasize gene knockouts for which a placental causality of embryonic heart defects has been demonstrated. This in-depth perspective provides much-needed insights while highlighting remaining gaps in knowledge that are essential for gaining a better understanding of the multi-facetted roles of the placenta in setting us up for a healthy start in life well beyond nutritional support alone.