• Hugo Creeth

Paternal Manipulation of Maternal Care

The Research

The original paper published in PLoS Biology can be found here: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2006599

A father’s genes are no longer thought to just provide a blueprint for the growth and development of their offspring. Research published on the 31 July in the open access journal PLOS Biology by scientists Dr Hugo Creeth, Professors Rosalind John and Anthony Isles from Cardiff University’s School of Biosciences finds that paternal genes can affect the type of care the offspring receives both before and after they are born.

The research team has been investigating the hormonal signals given off from the placenta during pregnancy. The placenta transports nutrients to the growing fetus during pregnancy and gives off hormonal signals in the mother’s bloodstream to establish and maintain a successful pregnancy. As well as being involved in nurturing the baby throughout the pregnancy, the placental signals are thought to be important for programming a mother’s behavior, preparing them for their new role as a parent.

These hormones are produced by placental cells called spongiotrophoblasts, whose proliferation (and therefore whose hormone output) is held in check by a gene called Phlda2.

Phlda2 affects a lineage of the placenta known as the spongiotrophoblast in mice. It releases vast quantities of placental lactogens, which are similar in structure to prolactin (the more well-known pregnancy hormone) but produced in much higher quantities from mid gestation. Placental hormones induce adaptation in the mother required for healthy fetal growth and suspected to play a role in inducing maternal instinct. Women are not born with a maternal instinct it is a behaviour which develops during pregnancy to prepare the mother-to-be for the new and demanding role of caring for her baby. Until now direct experimental evidence to support the theory that placental hormones trigger this “motherly love” by acting directly on the brain of the mother has been lacking.

But there is a twist; like most genes, the developing fetus has two copies of the Phlda2 gene, but unlike most genes, only one copy of Phlda2 is active. This is due to an evolutionarily intriguing phenomenon called genomic imprinting, whereby only the gene copy from one parent is switched on. In the case of Phlda2 it’s the father’s copy that’s silent.

Using genetically altered mice, the researchers asked what happened if both copies of the fetus’ Phlda2 gene were active (a “maternalized” condition) or if both were silent (a “paternalized” condition). They found that mothers exposed to pups with the highest Phlda2 activity (smallest spongiotrophoblast and therefore presumably reduced placental hormones) nursed and groomed their pups less and instead focused on nest building. Conversely, “paternalized” mothers, exposed to the lowest Phlda2 dose (largest spongiotrophoblast and therefore higher hormone levels), spent more time nurturing their pups, and less on housekeeping tasks. The authors also showed corresponding changes in two regions of the mother’s brain – the hypothalamus and hippocampus.

Imprinted genes are those that are expressed from either the maternal or paternal allele, whilst the other is silenced through epigenetic events that are initiated in the germline. Phlda2 is a key imprinted gene that is maternally expressed and paternally silenced in the placenta. Our lab showed that it regulates a key endocrine lineage of the placenta and is responsible for a late asymmetric growth restriction phenotype in mice.

Why is this important?

This work is the first of its kind to show that a gene from the father is able to manipulate placental signals during pregnancy. It looks like father’s have switched off this gene to increase the quality of care their offspring will receive from the mother. This is important when it comes to understanding the evolution of imprinting and its role in eutherian mammals. Parenthood can be seen as a conflict between the interests of the two parents, with the father (and his genes) favoring maximum investment in the offspring, potentially at the expense of the mother’s best interests. Thus the priorities of male and females don’t always match up—and in a way, imprinting is evolution timidly waving a white flag between the clashing sexes ideals. It’s all about balance. What both parents ultimately want, is the best for their offspring but not at the expense of their own health. This is why in mammals where the female has to carry and nurture the young her genes want to minimise the cost of her wellbeing but maximise her offspring’s fitness. The male on the other hand just wants the offspring to be as fit as possible at any cost to the mother. It’s an evolutionary tug of war, so to speak.

The authors speculate that this may have relevance to humans, as levels of Phlda2 gene activity vary between human pregnancies and inversely correlate with placental hormones. Changes in the mother’s priorities during gestation and after birth are critically important for the wellbeing of the new baby and their lifelong mental health.

The logic behind this idea and how their work could have significant implications for human mothers, as changes in a woman’s priorities during pregnancy and after birth are critically important for the wellbeing of the new baby. Women who do not undergo these changes may struggle to develop a maternal bond with their new born child and this could lead to issues such as postnatal depression, a damaging mental health disorder that sadly affects 1 in 12 new mothers.

“Our previous work has reported that a similar placental gene is linked to prenatal depression, and we are currently asking whether similar gene changes are associated with poor quality maternal care in the Grown in Wales Study” said Professor John, lead author of the study. “More work must be done to further our understanding in how this works in humans.” It is also known that children that do not receive high quality maternal care early in life are at higher risk of neurodevelopmental disorders and more likely to develop mental health issues when they grow up.

So although further work is required to bridge the gap into the human condition, other work being done in the group has shown that Phlda2 is expressed abnormally in the placenta of low birth weight human babies and that placental changes in a related gene called Peg3 are linked to prenatal depression, a mood disorder that tragically effects one in 7 pregnancies. It is this link that makes the work so exciting and opens the door to future research into genes that are paternally or maternally controlled impacting the care of the offspring and the lifelong health of both the mother and child.

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