Imprinted genes as master regulators of placental hormones

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Pregnancy is an extraordinary life-changing event full of physical and emotional changes to the mother. There are changes to maternal metabolism and the immune system required to support fetal growth and prevent fetal rejection. Considerable changes take place in the maternal brain preparing the mother for her new role in caring for her infant. All these changes require hormones produced by, or dependent on, the placenta. Ensuring normal placental development is therefore fundamentally important for the health of both the mother and her children.We are studying the development of cells in the placenta that manufacture placental hormones (endocrine cells). Specifically, we are interested in understanding how the number of endocrine cells is regulated by a family of genes called imprinted genes. Unlike most genes in mammals which are expressed from two copies, imprinted genes are expressed from one copy. This "monoallelic" expression is controlled by marks that are added to the genes called epigenetic marks. We do not fully understand why it is important for some genes in mammals to be expressed from only one copy but we do know that monoallelic expression makes imprinted genes highly vulnerable to mutation. A single genetic mutation can result in loss-of-function while exposure to prenatal adversity can alter epigenetic marks resulting in changes in the expression of imprinted genes.We have been studying the function of imprinted genes in placental development using mouse models. We discovered that maternally-expressed genes act to limit the number of endocrine cells in the placenta while paternally-expressed genes seem to have the opposite function. When the placenta has too few endocrine cells, expression of placental hormones is lower than normal and the fetus does not grow properly resulting in low birth weight. Mothers in these pregnancies also nurture their pups less. Both low birth weight and reduced maternal nurturing have been linked to adverse behavioural outcomes and we recently found that offspring from these pregnancies behave abnormally. These data highlight the importance of normal expression of these imprinted genes in the placenta for health in pregnancy and later in life, at least in mice.Here we will ask how imprinted genes work together to ensure that precisely the right number of cells develop for the optimal production of placental hormones. We will examine placenta with single or combined loss-of-function of the maternally-expressed Phlda2 gene and the paternally-expressed Peg3 gene to determine how many cells are present that express placental hormones. We will examine maternal serum to determine how these placental alterations alter hormones in the mother's blood. We will isolate single cells from the stem cell region of the placenta to identify and characterise progenitors for the endocrine lineages, and the impact of gene changes on their number and nature. We will use mouse trophoblast stem cells to establish the earliest consequence of these same modifications for development in culture and in chimeras. To translate our findings from mouse to human, we will modify the expression of PHLDA2 and PEG3 in human trophoblast stem cells to directly ask whether these genes regulate the development of placental endocrine lineages in humans. We will also ask whether there is a correlation between their expression and the composition of the placenta at term and the levels of serum placental lactogen using human placental samples we have already collected. In this way, we will establish whether these imprinted genes function antagonistically to regulate development of the placental endocrine lineages in both mice and human pregnancies. Through this greater understanding of placental development, our work will support optimal fetal growth and maternal wellbeing to improve lifelong health.