IMPC: Essential role of the GPI anchor biosynthesis pathway for early placentation and its impact on heart and brain development

Normal development of an embryo depends on a functional placenta, which is the organ responsible for all nutrient and oxygen supply to the growing baby during pregnancy. Placental development is tightly coupled to the development of embryonic organ systems. Mouse studies have shown that heart and brain defects in particular are often observed in association with placental failures. In some cases these embryonic pathologies can even be caused solely by the abnormal placenta and, consequently, can be rescued when placental function is restored. Despite this vital function, the importance of the placenta for healthy pregnancy and reproductive success has often been overlooked. In fact our efforts have identified that a far greater number of genes is involved in formation of a functional placenta than has been previously appreciated. In the course of our long-standing interest in this field, we have found that a particular molecular pathway that enables proteins to be anchored to the surface of cell membranes where they may function to recognize and direct specific signals into the cell, plays a pivotal role in placental development. Intriguingly, members of this same biochemical family have been associated in humans with congenital heart defects and neurodevelopmental pathologies resulting in mental retardation, opening up the possibility that these defects may in fact originate in an early placental abnormality. In this work, we will study two components of this pathway to identify their precise role in placental development, using the mouse as a model system. We will investigate very early stages of gestation in which the foundations are laid down for a healthy pregnancy later on, to determine which specific steps in placenta formation are affected. Taking advantage of mouse genetics, we will also study whether the defective placenta is the sole cause of the severe embryonic defects observed. In parallel, using genome editing technology we will establish placental stem cell lines that carry mutations in these factors, which will allow us to elucidate, in the longer term, which particular membrane-bound proteins and which signalling cues are crucial for these developmental processes. This work is of fundamental importance to gain a better understanding of placental development and its impact on formation of key organs in the baby, notably the heart and the brain.

Normal development of an embryo depends on a functional placenta, which is the organ responsible for all nutrient and oxygen supply to the growing baby during pregnancy. Placental development is tightly coupled to the development of embryonic organ systems. Mouse
studies have shown that heart and brain defects in particular are often observed in association with placental failures. In some cases
these embryonic pathologies can even be caused solely by the abnormal placenta and, consequently, can be rescued when placental
function is restored.

Despite this vital function, the importance of the placenta for healthy pregnancy and reproductive success has often been overlooked. In
fact our efforts have identified that a far greater number of genes is involved in formation of a functional placenta than has been
previously appreciated. In the course of our long-standing interest in this field, we have found that a particular molecular pathway that
enables proteins to be anchored to the surface of cell membranes where they may function to recognize and direct specific signals into
the cell, plays a pivotal role in placental development. Intriguingly, members of this same biochemical family have been associated in
humans with congenital heart defects and neurodevelopmental pathologies resulting in mental retardation, opening up the possibility that
these defects may in fact originate in an early placental abnormality.

In this work, we will study two components of this pathway to identify their precise role in placental development, using the mouse as a
model system. We will investigate very early stages of gestation in which the foundations are laid down for a healthy pregnancy later on,
to determine which specific steps in placenta formation are affected. Taking advantage of mouse genetics, we will also study whether the
defective placenta is the sole cause of the severe embryonic defects observed. In parallel, using genome editing technology we will
establish placental stem cell lines that carry mutations in these factors, which will allow us to elucidate, in the longer term, which
particular membrane-bound proteins and which signalling cues are crucial for these developmental processes.

This work is of fundamental importance to gain a better understanding of placental development and its impact on formation of key organs in the baby, notably the heart and the brain.