Hugo D. J. Creeth

Beckwith–Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2, which is imprinted in mice but not in humans. To overcome this issue, we generated a novel model combining a truncation of distal chromosome 7 allele (DelTel7) with transgenic rescue of Ascl2 expression. This novel model recapitulated placentomegaly associated with BWS, but did not lead to fetal overgrowth.

Hormones from the fetally derived placenta signal to the mother throughout pregnancy to ensure optimal fetal growth and prepare the mother for her new role in nurturing her offspring. Through evolution, placental hormones have under gone remarkable diversification and species-specific expansions thought to be due to constant rebalancing of resource allocation between mother and offspring. Genomic imprinting, an epigenetic process in which parental germlines silence genes in the offspring, is thought to be the physical embodiment of a second conflicting interest, between the male and female mammal. Several genes silenced by paternal imprints normally function to limit the placental endocrine lineages of the mouse placenta. We hypothesized that paternal imprinting has adapted to overcome the rapid evolution of placental hormone gene families by directly regulating the lineages that express these hormones rather than individual hormones. This predicts the existence of genes maternally silenced in the offspring counteracting the influence of the paternal imprint. Here we report on the consequences of loss of function of Paternally expressed gene 3 (Peg3), on placental endocrine lineages. Mutant male placenta displayed a marked loss of the spongiotrophoblast, a key endocrine lineage of the placenta, and the glycogen cell lineage alongside reduced stores of placental glycogen and changes in expression of the normal repertoire of placental hormones. Peg3 is known to transcriptionally repress placental hormone genes. Peg3 consequently both positively and negatively regulates placental hormones through two independent and opposing mechanisms. Female placenta showed moderate response to loss of Peg3 with minor alterations to the junctional zone lineages and few changes in gene expression. These data highlight the important fact that female placenta compensate for the loss of Peg3 better than male placenta. This work lends further support to our novel hypothesis that the parental genomes are competing over the endocrine function of the mouse placenta and further suggests that a conflict between males and females begins in utero.

In mammals, mothers are the primary caregiver, programmed, in part, by hormones produced during pregnancy. High-quality maternal care is essential for the survival and lifelong health of offspring. We previously showed that the paternally silenced imprinted gene pleckstrin homology-like domain family A member 2 (Phlda2) functions to negatively regulate a single lineage in the mouse placenta called the spongiotrophoblast, a major source of hormones in pregnancy. Consequently, the offspring’s Phlda2 gene dosage may influence the quality of care provided by the mother. Here, we show that wild-type (WT) female mice exposed to offspring with three different doses of the maternally expressed Phlda2 gene—two active alleles, one active allele (the extant state), and loss of function—show changes in the maternal hypothalamus and hippocampus during pregnancy, regions important for maternal-care behaviour. After birth, WT dams exposed in utero to offspring with the highest Phlda2 dose exhibit decreased nursing and grooming of pups and increased focus on nest building. Conversely, ‘paternalised’ dams, exposed to the lowest Phlda2 dose, showed increased nurturing of their pups, increased self-directed behaviour, and a decreased focus on nest building, behaviour that was robustly maintained in the absence of genetically modified pups. This work raises the intriguing possibility that imprinting of Phlda2 contributed to increased maternal care during the evolution of mammals. Female mammals are primed during pregnancy for their new role as a mother caring for their newborn. Indirect evidence suggests that this behaviour is, in part, instructed by hormones produced by the foetally derived placenta. We previously reported that the Phlda2 gene controls the size of the placental endocrine compartment that produces hormones. Phlda2 is subject to the remarkable epigenetic process called genomic imprinting, in which one parental allele is switched off. In the case of Phlda2, this is the paternal allele. This raises the intriguing possibility that the father’s genome influences the quality of care that offspring receive from their mothers. Here, we show via genetic manipulation of pup embryos that female mice pregnant with pups carrying the highest dose of Phlda2 favour nest building over caring for their young or themselves. In contrast, dams exposed to the lowest Phlda2 dose while pregnant prioritise nurturing and grooming of their young and personal grooming. These changes in maternal focus suggest the possibility that imprinting of Phlda2 contributed to enhanced maternal care in mammals. This study also presents a unique example of how the genetic makeup of offspring can influence maternal behaviour.

Depression and anxiety are the most common mental health conditions during pregnancy and can impair the normal development of mother-infant interactions. These adversities are associated with low birth weight and increased risk of behavioural disorders in children. We recently reported reduced expression of the imprinted gene PATERNALLY EXPRESSED GENE 3 (PEG3) in placenta of human infants born to depressed mothers. Expression of Peg3 in the brain has previously been linked maternal behaviour in rodents, at least in some studies, with mutant dams neglecting their pups. However, in our human study decreased expression was in the placenta derived from the fetus. Here, we examined maternal behaviour in response to reduced expression of Peg3 in the feto-placental unit. Prenatally we found novelty reactivity was altered in wild-type females carrying litters with a null mutation in Peg3. This behavioural alteration was short-lived and there were no significant differences the transcriptomes of either the maternal hypothalamus or hippocampus at E16.5. In contrast, while maternal gross maternal care was intact postnatally, the exposed dams were significantly slower to retrieve their pups and displayed a marked increase in anxiety. We also observed a significant reduction in the isolation-induced ultrasonic vocalizations (USVs) emitted by mutant pups separated from their mothers. USVs are a form of communication known to elicit maternal care suggesting Peg3 mutant pups drive the deficit in maternal behaviour. These data support the hypothesis that reduced placental PEG3 in human pregnancies occurs as a consequence of prenatal depression but leaves scope for feto-placental Peg3 dosage, during gestation, influencing aspects of maternal behaviour.

Substantial data demonstrate that the early‐life environment, including in utero, plays a key role in later life disease. In particular, maternal stress during pregnancy has been linked to adverse behavioural and emotional outcomes in children. Data from human cohort studies and experimental animal models suggest that modulation of the developing epigenome in the foetus by maternal stress may contribute to the foetal programming of disease. Here, we summarise insights gained from recent studies that may advance our understanding of the role of the placenta in mediating the association between maternal mood disorders and offspring outcomes. First, the placenta provides a record of exposures during pregnancy, as indicated by changes in the placental trancriptome and epigenome. Second, prenatal maternal mood may alter placental function to adversely impact foetal and child development. Finally, we discuss the less well established but interesting possibility that altered placental function, more specifically changes in placental hormones, may adversely affect maternal mood and later maternal behaviour, which can also have consequence for offspring well‐being.