Establishment of a functional placenta - a prerequisite for lifelong health of offspring and motherLeading on from the regulation of the trophoblast stem cell niche, another core aspect of our research focuses on genetic and epigenetic requirements for normal placentation during subsequent development. As part of the WT “Deciphering the Mechanisms of Developmental Disorders” consortium, we are conducting a systematic screen for placental defects in embryonic lethal mouse mutants (below, left). This will, for the first time, provide a global overview of the collection of genes that are jointly necessary to make a functional placenta.
An example of an early placental defect that will cause embryonic lethality, as detected in a mouse mutant strain analysed as part of the “Deciphering the Mechanisms of Developmental Disorders” (DMDD) phenotyping screen.
An early mouse embryo (E7.5-E8.5) within its implantation site in the uterus, stained for a giant cell marker gene. Giant cells (GCs, stained in dark purple) line the entire implantation site and invade into the surrounding maternal uterine tissue in the area indicated by the dashed box. (B) Close-up view of the invasion zone. Arrows indicate the direction of giant cell invasion. (C) Trophoblast tissue cultured in vitro and stained for a microtubule marker (red) and the nucleus (blue). Note the size of the giant cell in comparison to surrounding cells.
We are also interested in how specific signaling pathways can affect trophoblast differentiation to build a functional placenta, and how some of these pathways may be altered with advanced maternal age and therefore lead to an increased frequency of placental pathologies. We are investigating how these signaling pathways intersect with the epigenome to propagate any such alterations both within the embryo as well as the placenta.
As the sole source of nutrient supply for the growing embryo, the placenta has a crucial role in supporting embryonic growth and survival. Intrauterine conditions are known to have permanent effects on adult body composition, physiology and metabolism. Low birth weight, for example, is now known to be associated with increased rates of cardiovascular disease and diabetes. By understanding, modeling and being able to manipulate key trophoblast differentiation pathways we will learn about the mechanisms that ensure a normal progression of pregnancy, healthy babies and mothers as well as health during later adult life.