The Paternal Manipulation of Maternal Care

A father's genes are now thought to play a vital role in programming maternal care after birth through the action of the often overlooked placenta. Here we take a look at how this completely novel idea came to fruition. Then the what's? why's? and how's? of the research and what is happening next.

Go to the profile of Hugo Creeth
Aug 02, 2018
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The Beginning

This study began its life on a train journey 7 years ago. After an interesting Royal Society Meeting “Phenotype and the Flexible Epigenome” in London, co-organisers Rosalind John and Anthony Isles were travelling back to Cardiff on the train. During this 2 hour journey Ros was discussing some recent research in her lab which showed that imprinted genes expressed in the mouse placenta regulate the production of placental hormones and mentioned that these genes might therefore have an effect on maternal care behaviour. This was not a completely crazy idea as placental hormones have long been known to be important for programming maternal care in non-pregnancy rodents. However, the idea that a gene expressed in the offspring’s placenta could influence maternal behaviour was entirely novel. Having successfully collaborated on another project, she asked Anthony if he thought this might be an interesting new joint project to pursue.
 
A short time later I heard a talk by Ros and the idea also jumped out at me. I approached her after the talk to ask if there was a chance I could work with her and develop this story. She downplayed the idea and said… “I am sorry but it is too risky”. In a world where funding is everything in science, Ros was right. In my naivety, however, I persisted. Eventually Ros was persuaded to take me on. Under her supervision I was let loose to take up the research for my Master’s and then my PhD. 

The rest, as they say, is history.

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

Our research group, now named PREG lab (Pregnancy Research Epigenetics Group – my idea!) was formed, with Ros spearheading it and Anthony providing his expert neuroscience advice. We all work on imprinted genes. 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. The lineage of the placenta it affects is 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.
 
The major aim in our research was to address this gap in our knowledge. We utilised a novel experimental system that drew on our previous research into the imprinted gene Phlda2’s role in negatively regulating placental hormones. The Phlda2 phenomenon allowed us to develop the novel genetic system, where placental hormones were manipulated to be higher or lower than normal based on the dosage of Phlda2. We showed that new mother mice exposed in pregnancy to a higher hormones during gestation spent more time caring for their offspring while mothers exposed to lower signal spent more time on “housekeeping” tasks and less time nurturing and grooming their offspring, independent of the mothers own genotype. We further showed that when these mothers were presented with offspring from a different mother, they maintained their enhanced caring behaviour indicating prenatal programming. This was supported by gene changes in two key brain regions associated with maternal behaviour, the hippocampus and the hypothalamus, before birth. 


 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. 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.
 
This 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. Similarly it is 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.


Although further work is required to bridge the gap into the human condition, other work being done in our group showed 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.

Finally 

Like most research it was a tumultuous few years not least because I was not officially funded by anyone to do a PhD at the start and if it wasn't for the several late nights that all three of us spent writing applications to various pots of money this project wouldn't have gotten of the ground. I am therefore incredibly thankful to the Ewan Maclean Scholarship, The Waterloo Foundation and Cardiff University all of whom provided me with a means to carry on working on a project that still fascinates me. 

As for me, I have now graduated with my PhD and look back with fondness at the conversations I had with Ros and Anthony all those years ago, and I am forever grateful that they took the risk (or was it pity? I can’t really remember) and that even through the hard times we perceived. I am hoping, that as I continue to work for in PREG lab as a post-doc, I will be able to discover more about the remarkable phenomenon and pass on an knowledge I have acquired along the way to those just starting out on the path into scientific research.

Go to the profile of Hugo Creeth

Hugo Creeth

Post-Doc, Cardiff University

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