Fetuses use father’s ‘greedy’ gene to help in nutritional tug-of-war with mother, University of Cambridge scientists discover

Unborn babies use a copy of a ‘greedy’ gene inherited from their father to help them in the nutritional tug-of-war with their mothers, Cambridge scientists have found.

A fetus effectively ‘remote controls’ the mother’s metabolism in order to prompt her to release as many nutrients as possible.

While the mother’s body wants the baby to survive, it also needs to keep sufficient glucose and fats circulating in her system for her own health, for the delivery of the baby, breastfeeding and future reproduction.

A new University of Cambridge study published on Tuesday (July 11) explores how the placenta communicates with the mother through the release of hormones so that she will accommodate her baby’s growth.

The placenta develops in female mammals to support the growth of the fetus.

To study it, scientists selectively altered the signalling cells in the placenta of pregnant mice that tell mothers to allocate nutrients to the developing fetus.

They showed baby’s genes from the father tend to promote fetal growth and those controlled by the mother tend to limit fetal growth.

Dr Miguel Constancia, MRC Investigator based at the Wellcome-MRC Institute of Metabolic Science and co-senior author of the paper, said: “The baby’s remote control system is operated by genes that can be switched on or off depending on whether they are a ‘dad’s’ or ‘mum’s’ gene’ - the so-called imprinted genes.

“Genes controlled by the father are ‘greedy’ and ‘selfish’ and will tend to manipulate maternal resources for the benefit of the fetuses, so to grow them big and fittest. Although pregnancy is largely cooperative, there is a big arena for potential conflict between the mother and the baby, with imprinted genes and the placenta thought to play key roles.”

Co-author Prof Amanda Sferruzzi-Perri, professor in fetal and placental physiology and a fellow of St John’s College, said: “It’s the first direct evidence that a gene inherited from the father is signalling to the mother to divert nutrients to the fetus.

“Those genes from the mother that limit fetal growth are thought to be a mother’s way of ensuring her survival, so she doesn’t have a baby that takes all the nutrients and is too big and challenging to birth. The mother also has a chance of having subsequent pregnancies potentially with different males in the future to pass on her genes more widely.”

Researchers deleted the expression of a key imprinted gene, called Igf2, which provides instructions for making the protein called Insulin Like Growth Factor 2.

Like the hormone insulin, which makes and controls glucose levels in our circulation, this gene promotes fetal growth and plays a key part in the development of fetal tissues such as the placenta, liver and brain.

Dr Jorge Lopez-Tello, a lead author of the study based at the university’s Department of Physiology, Development and Neuroscience, said: “If the function of Igf2 from the father is switched off in signalling cells, the mother doesn’t make enough glucose and lipids – fats – available in her circulation. These nutrients therefore reach the fetus in insufficient amounts and the fetus doesn’t grow properly.”

Deleting Igf2 from the placenta’s signalling cells affected the production of other hormones that modulate the way the mother’s pancreas produces insulin, and how her liver and other metabolic organs respond, the scientists found.

“We found Igf2 controls the hormones responsible for reducing insulin sensitivity in the mother during pregnancy. It means the mother’s tissues don’t absorb glucose so nutrients are more available in the circulation to be transferred to the fetus,” explained Prof Sferruzzi-Perri.

“Until now, we didn’t know that part of the Igf2 gene’s role is to regulate signalling to the mother to allocate nutrients to the fetus.”

Babies with Igf2 gene defects can be overgrown or have stunted growth.

The mice studied were smaller at birth and their offspring showed early signs of diabetes and obesity in later life.

“Our research highlights how important the controlled allocation of nutrients to the fetus is for the lifelong health of the offspring, and the direct role the placenta plays,” added Prof Sferruzzi-Perri.

“The placenta is an amazing organ. At the end of pregnancy, the placenta is delivered by the mother, but the memories of how the placenta was functioning leaves a lasting legacy on the way those fetal organs have developed and then how they’re going to function through life.”

The next stage for the research is to understand how placental hormones are controlled by Igf2 and what those hormones are doing.

Future work could help scientists discover new strategies to target the placenta to improve health outcomes for mums and babies.

The findings by researchers from the Centre for Trophoblast Research at Cambridge’s Department of Physiology, Development and Neuroscience and the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science, have been published in Cell Metabolism.