Communication between mother and fetus : Imprinting and endocrine adaptations to pregnancy

Context:
Pregnancy is associated with high rates of morbidity and mortality despite broad advances in healthcare over the last 50 years. In addition, as rates of obesity and diabetes increase in the general population, the outcomes of pregnancy have worsened and maternal and fetal health remains a significant public health issue. Underlying this is a lack understanding of how energy is diverted to the fetus from the mother during gestation, and how this goes wrong as a result of the interaction between altered maternal diet and genetic factors. In addition, there are few diagnostic tools available to detect when the energy supply to the fetus is compromised, and consequently paediatric clinicians have a paucity of information upon which to act to improve outcomes for pregnant women and their children.
Aims and objectives:
We propose to increase our basic knowledge about how the fetus gains resources from the mother during pregnancy. In late gestation, when the fetus is growing very rapidly, the mother must be able to deliver maximal resources. One way in which the mother's body knows to do this is because the placenta releases hormones into the maternal circulation that signal redistribution of maternal nutrients obtained from food. For example, during late gestation the mother becomes less likely to convert excess dietary glucose into stored fat, and instead the glucose is transported across the placenta to become fuel for fetal growth. We work on a signalling molecule called DLK1, which increases in concentration in maternal blood during pregnancy in mice. Others have found that this increase in maternal DLK1 also occurs during human pregnancy. We recently proved (using genetically modified mice that have a mutation in their Dlk1 gene) that this molecule must come from the fetus or the placenta. We propose to discover if DLK1 is a placental hormone, and if the human placenta is also a source of DLK1. In non-pregnant females the amount of DLK1 in the blood is low. We found that genetically modified mice that make high levels of DLK1 store less energy as fat, and use fats rather than glucose as an energy source. This is very similar to what happens in pregnancy when DLK1 is naturally high. We hypothesise is that the fetus uses DLK1 as a signal to instruct the mother to make more energy available for fetal growth. We will test this hypothesis, and aim to discover how this potentially novel hormone works.

DLK1 is encoded by a member of a group of genes that are regulated in an unusual way. Each gene in the genome is present in two copies, one inherited from the father and the other from the mother. In most circumstances both of these genes form the template for producing proteins. However, a group of ~100 genes in the mammalian genome are only expressed from one parental copy, and the other copy is silenced, the imprinted genes. Imprinted genes are known to encode molecules that have crucial functions in growth and development, as well as in metabolic processes during adulthood.

The maternal pituitary gland is known to change its size and hormone output during pregnancy. DLK1, and other imprinted products are expressed in the pituitary gland, and are regulated by pregnancy. We would like to understand if imprinted genes mediate maternal pituitary function during pregnancy, and how they are activated during this period. This is important because if the maternal pituitary gland does not adapt appropriately to pregnancy the growth and wellbeing of both mother and fetus are compromised.

Potential applications and benefits.
It is likely that maternal DLK1 levels differ between normal pregnancies and those where fetal growth is compromised such as in preeclampsia and intrauterine growth restriction. Our hope is that by understanding its source and function we could in the future use maternal DLK1 levels as a novel non-invasive marker of fetal well being, informing clinical practice to improve pregnancy outcomes

Late gestation in mammals is accompanied by multiple adaptations of maternal energy homeostasis, to divert maternal resources towards the supply of glucose for the rapidly-growing fetus. These adaptations include a reduction in hepatic lipogenesis and adipose deposition. During pregnancy there is considerable remodelling of the anterior pituitary which causes an increase in somatolactotrophic cells. In addition, the placenta secretes placental lactogen and a pregnancy-specific version of growth hormone (GH). Since GH and its family members cause insulin resistance and inhibit hepatic lipogenesis, increased activity of the pituitary-placental axis is thought to modulate maternal adaptations in late pregnancy.

The product of the imprinted Delta-like homologue 1, DLK1, is a signalling molecule that reaches a high concentration in maternal serum from mid to late pregnancy in rodents and humans. We recently discovered that that the conceptus is the source, and that DLK1 may therefore be a novel endocrine signal from fetus to mother. Our studies with genetically-modified mice show that endocrine DLK1 acts to inhibit hepatic lipogenesis and increase beta oxidation in skeletal muscle. Moreover, elevated DLK1 causes an increase in pituitary GH secretion.

Using genetic models of altered Dlk1 gene dosage, we will test the hypothesis that DLK1 produced by the conceptus alters the activity of the pituitary-placental axis, modulating important metabolic changes in maternal resource allocation. Moreover, Dlk1 is a member of an imprinted gene network that we propose acts in the maternal pituitary gland during pregnancy. We wish to understand the regulation of this network.

Understanding the function of DLK1 and other imprinted genes in pregnancy has potential clinical value since failures of growth and timely development occur when maternal resource allocation is disrupted. Moreover, maternal serum DLK1 could be used as a non-invasive biomarker of poor pregnancy outcome.

We will seek to impact the wider community in 3 ways:
1) The outcome of this project will lead to greater understanding of how failures of energy allocation to the fetus bring about common complications of pregnancy such as intrauterine growth restriction and placental insufficiency. This understanding could ultimately lead to new diagnostic tests/interventions to treat these disorders. Production of such a test will also have value to the economy.
2) Disseminating basic research findings and technical skills to the medical/clinical training community.
3) Public dissemination of science. We will work with Games Design students at the University of East London to prototype a computer game on the theme of 'Maternal-Fetal Interaction'. A successful prototype will be publicised on the UEL Games website and potentially be pitched for further development to a public dissemination funding body such as the Wellcome Trust.