The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources

Abstract

Imprinted genes, which are expressed from a single parental allele in response to epigenetic marks first established in the germline, function in a myriad of processes to regulate mammalian development. Recent work suggests that imprinted genes may regulate the signalling function of the placenta by modulating the size of the endocrine compartment. Here we provide in vivo evidence that this hypothesis is well founded. Elevated expression of the imprinted Pleckstrin homology-like domain, family a, member 2 (Phlda2) gene drives a reduction of the spongiotrophoblast endocrine compartment, diminished placental glycogen and asymmetric foetal growth restriction. Using both loss-of-function and gain-in-expression mouse models, here we further show that Phlda2 exclusively modulates the spongiotrophoblast compartment of the placenta without significantly altering the composition of the trophoblast giant cell endocrine lineages that share a common progenitor with this lineage. Additionally, we show that Phlda2 loss-of-function placentae contain nearly three times more placental glycogen than non-transgenic placentae. Remarkably, relative to a fully wild type scenario, wild type placentae also accumulate excessive glycogen. While loss-of-function of Phlda2 increased both placental weight and placental glycogen, the weight of both mutant and non-transgenic fetuses was lower than that found in a fully wild type scenario indicating that excessive glycogen accumulation comes at the cost of foetal growth. This work firstly highlights a novel signalling function for the spongiotrophoblast in stimulating the global accumulation of placental glycogen. Furthermore, this work suggests that Phlda2 manipulates the placenta's demands for maternal resources, a process that must be tightly regulated by epigenetic marks to ensure optimal foetal growth.

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

“…) and Phlda2 (an inhibitory regulator for placental glycogen storage) (Tunster et al . , ) was decreased in DHT+insulin‐treated and DHT‐treated pregnant rats, while there was a trend towards lower Gjb3 and Phlda2 mRNA expression in insulin‐treated pregnant rats (Fig. C ).…”

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery

“…Among them the genes ATF4 1617, C3 1819 , PHLDA2 20, GPX4 21 and ICAM1 22 have been previously linked with the pathogenesis of pregnancy loss. Additionally, GPX4 has been implicated in preeclampsia23, PHLDA2 242526 and SLC16A2 2728 in fetal growth restriction, CD74 and LAPTM5 in preterm premature rupture of membranes29 (details and full list of references in Supplementary Data S3b). Several short-listed genes function in trophoblast invasion, proliferation and syncytialization processes ( EGR1, PDLIM1, MAPK3 ).…”

“…3B). Some of these genes are dysregulated in multiple adverse pregnancy complications, such as imprinted and maternally expressed gene PHLDA2 , which is linked to RPL, fetal growth restriction (FGR) and preeclampsia20242526. A number of pregnancy complications including RPL, FGR, hypertensive disorders in pregnancy and preterm birth are associated with excessive or misdirected complement activation, where C3 has a distinct role in early pregnancy18.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…The best evidence in mice that placental hormones regulate fetal growth is that of the pleckstrin homology-like domain, family A member 2 gene which regulates the fetal growth by influencing the number of endocrine cells in the placenta. 176 …”