Imprinted genes and the regulation of placental endocrine function: Pregnancy and beyond

Roshan, John

doi:10.1016/j.placenta.2017.01.099

Cited by 43 publications

(32 citation statements)

References 55 publications

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“…In conclusion, we report that loss of function of the imprinted Peg3 gene results in the loss of both the spongiotrophoblast and glycogen cell lineages. This supports Haig’s original prediction that imprinted genes will be in conflict over the endocrine function of the placenta ( Haig, 1996 ) and our hypothesis that this is achieved through the regulation of placental lineages that manufacture hormones ( John and Hemberger, 2012 ; John, 2013 , 2017 ). The sexually dimorphic response of the placenta to loss-of-function of Peg3 and the remarkable fact that Peg3 appears to be required both for the expression and repression of key placental hormones adds additional layers of complexity to studying the function of Peg3 both in pregnancy and mammalian evolution.…”

Section: Discussionsupporting

confidence: 89%

Peg3 Deficiency Results in Sexually Dimorphic Losses and Gains in the Normal Repertoire of Placental Hormones

Tunster

Boqué-Sastre

McNamara

et al. 2018

Front. Cell Dev. Biol.

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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.

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Section: Discussionsupporting

confidence: 89%

Peg3 Deficiency Results in Sexually Dimorphic Losses and Gains in the Normal Repertoire of Placental Hormones

Tunster

Boqué-Sastre

McNamara

et al. 2018

Front. Cell Dev. Biol.

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“…Phlda2 is expressed from the maternal allele primarily in the placenta [ 47 , 48 ] and encodes a pleckstrin homology (PH) domain–only protein [ 49 ] that functions to inhibit cell proliferation by repressing AKT activation [ 50 ]. Early in mouse placental development, Phlda2 supresses the proliferation of the spongiotrophoblast [ 51 ]. Doubling the Phlda2 gene dosage (potentially resembling the ancient preimprinted state) by means of a bacterial artificial chromosome (BAC) transgene reduces the contribution of the spongiotrophoblast lineage to the mature placenta by approximately 50%, whereas loss of expression by knockout (KO) of the maternal allele results in a 2-fold expansion of this lineage [ 41 , 52 – 54 ].…”

Section: Introductionmentioning

confidence: 99%

Maternal care boosted by paternal imprinting in mammals

et al. 2018

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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.

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“…In addition, imprinted gene products can modulate labyrinth size and the surface area for exchange [Igf2 (Sibley et al, 2004) and Growth factor bound protein 10 (Grb10; Charalambous et al, 2010)] as well as vascular branching density [Aquaporin (Guo et al, 2016)]. Placental imprinted genes can also directly influence maternal physiology by controlling the differentiation of the trophoblast-derived endocrine cells (reviewed in John, 2017).…”

Section: Fetal Resource Acquisition Via the Placentamentioning

confidence: 99%

Genomic imprinting, growth and maternal–fetal interactions

Cassidy

Charalambous

2018

Journal of Experimental Biology

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In the 1980s, mouse nuclear transplantation experiments revealed that both male and female parental genomes are required for successful development to term (McGrath and Solter, 1983; Surani and Barton, 1983). This non-equivalence of parental genomes is because imprinted genes are predominantly expressed from only one parental chromosome. Uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith–Wiedemann and Silver–Russell syndromes (reviewed in Peters, 2014). More than 100 imprinted genes have now been discovered and the functions of many of these genes have been assessed in murine models. The first such genes described were the fetal growth factor insulin-like growth factor 2 (Igf2) and its inhibitor Igf2 receptor (Igf2r) (DeChiara et al., 1991; Lau et al., 1994; Wang et al., 1994). Since then, it has emerged that most imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have been shown to affect postnatal growth and energy homeostasis. Given that abnormal birthweight correlates with adverse adult metabolic health, including obesity and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to fetal and postnatal growth, with implications for lifelong health and disease.

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Imprinted genes and the regulation of placental endocrine function: Pregnancy and beyond

Cited by 43 publications

References 55 publications

Peg3 Deficiency Results in Sexually Dimorphic Losses and Gains in the Normal Repertoire of Placental Hormones

Peg3 Deficiency Results in Sexually Dimorphic Losses and Gains in the Normal Repertoire of Placental Hormones

Maternal care boosted by paternal imprinting in mammals

Genomic imprinting, growth and maternal–fetal interactions

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