Fetal expression of imprinted genes regulates placental growth in late pregnancy

Scientists have determined the expression of two genes in the fetus, one from the mother and one from the father, is essential for regulation of blood vessel growth in the placenta.

IGF2 is a growth factor that is known to increase in the umbilical cord during the third trimester of pregnancy in humans. Low levels of the protein in the umbilical cord are associated with smaller babies and higher levels are associated with larger babies. Babies born small or large for their gestational age are more likely to experience health problems or even die. University of Cambridge scientists have now identified a key role for the protein IGF2 in controlling the development of blood vessels in the placenta during late pregnancy in mice.

'As it grows in the womb, the fetus needs food from its mum, and healthy blood vessels in the placenta are essential to help it get the correct amount of nutrients' said first author Dr Ionel Sandovici, from the department of obstetrics and gynaecology, University of Cambridge. 'We've identified one way that the fetus uses to communicate with the placenta to prompt the correct expansion of these blood vessels. When this communication breaks down, the blood vessels don't develop properly and the baby will struggle to get all the food it needs.'

IGF2 is the signal that the scientists believe is responsible for ensuring placental supply of nutrients meets fetal demand. Interestingly, IGF2 is always made from the copy of the igf2 gene inherited from the father, while its receptor IGF2R always made using the copy of the igf2r gene that came from the mother. This phenomenon of gene expression being dependent on which parent it was inherited from is known as 'imprinting'.

Lead author Dr Miguel Constância, an associate professor in reproductive biology at the University of Cambridge, commented: 'One theory about imprinted genes is that paternally-expressed genes are greedy and selfish. They want to extract the most resources as possible from the mother. But maternally-expressed genes act as countermeasures to balance these demands.'

To determine the role of IGF2 in placental growth researchers knocked out the igf2 gene and/or the igf2r gene in the fetus and placenta. They found that IGF2 expression was mediated by the IGF2R receptor, and when IGF2 was not expressed by the fetus there was restriction of placental growth in late pregnancy.

They also found that IGF2 acted as a signal for other genetic pathways involved in cell proliferation and blood vessel growth, and proposed a mechanism whereby IGF2 signalling from the fetus drives growth of the placenta in order to provide adequate nutrition for fetal growth. Results were published in Developmental Cell.

'In our study, the father's gene drives the fetus's demands for larger blood vessels and more nutrients, while the mother's gene in the placenta tries to control how much nourishment she provides. There's a tug-of-war taking place, a battle of the sexes at the level of the genome,' explained Dr Constância.