Loss of imprinting of the Igf2-H19 ICR1 enhances placental endocrine capacity via sex-specific alterations in signalling pathways in the mouse

ABSTRACT Imprinting control region (ICR1) controls the expression of the Igf2 and H19 genes in a parent-of-origin specific manner. Appropriate expression of the Igf2-H19 locus is fundamental for normal fetal development, yet the importance of ICR1 in the placental production of hormones that promote maternal nutrient allocation to the fetus is unknown. To address this, we used a novel mouse model to selectively delete ICR1 in the endocrine junctional zone (Jz) of the mouse placenta (Jz-ΔICR1). The Jz-ΔICR1 mice exhibit increased Igf2 and decreased H19 expression specifically in the Jz. This was accompanied by an expansion of Jz endocrine cell types due to enhanced rates of proliferation and increased expression of pregnancy-specific glycoprotein 23 in the placenta of both fetal sexes. However, changes in the endocrine phenotype of the placenta were related to sexually-dimorphic alterations to the abundance of Igf2 receptors and downstream signalling pathways (Pi3k-Akt and Mapk). There was no effect of Jz-ΔICR1 on the expression of targets of the H19-embedded miR-675 or on fetal weight. Our results demonstrate that ICR1 controls placental endocrine capacity via sex-dependent changes in signalling.

Histology Atlas of the Developing Mouse Placenta

The use of the mouse as a model organism is common in translational research. This mouse–human similarity holds true for placental development as well. Proper formation of the placenta is vital for development and survival of the maturing embryo. Placentation involves sequential steps with both embryonic and maternal cell lineages playing important roles. The first step in placental development is formation of the blastocyst wall (approximate embryonic days [E] 3.0-3.5). After implantation (∼E4.5), extraembryonic endoderm progressively lines the inner surface of the blastocyst wall (∼E4.5-5.0), forming the yolk sac that provides histiotrophic support to the embryo; subsequently, formation of the umbilical vessels (∼E8.5) supports transition to the chorioallantoic placenta and hemotrophic nutrition. The fully mature (“definitive”) placenta is established by ∼E12.5. Abnormal placental development often leads to embryonic mortality, with the timing of death depending on when placental insufficiency takes place and which cells are involved. This comprehensive macroscopic and microscopic atlas highlights the key features of normal and abnormal mouse placental development from E4.5 to E18.5. This in-depth overview of a transient (and thus seldom-analyzed) developmental tissue should serve as a useful reference to aid researchers in identifying and describing mouse placental changes in engineered, induced, and spontaneous disease models.

MicroRNA changes in the mouse placenta due to bisphenol A exposure

The aim of this study was to determine small RNA expression changes in mouse placenta induced by bisphenol A (BPA) exposure. The methods included exposing female mice to BPA two weeks prior to conception through gestational day 12.5; whereupon fetal placentas were collected, frozen in liquid nitrogen and stored at -80°C. Small RNAs were isolated and used for small RNA-sequencing. The results showed that 43 small RNAs were differentially expressed. Target mRNAs were closely aligned to those expressed by thymus and brain, and pathway enrichment analyses indicated that such target mRNAs regulate neurogenesis and associated neurodevelopment processes. The major conclusions are that BPA induces several small RNAs in mouse placenta that might provide biomarkers for BPA exposure. Further, the placenta might affect fetal brain development through the secretion of miRs.

Mapping cis-regulatory elements in the midgestation mouse placenta

The placenta is a temporary organ that provides the developing fetus with nutrients, oxygen, and protection in utero. Defects in its development, which may be caused by misregulated gene expression, can lead to devastating outcomes for the mother and fetus. In mouse, placental defects during midgestation commonly lead to embryonic lethality. However, the regulatory mechanisms controlling expression of genes during this period have not been thoroughly investigated. Therefore, we generated and analyzed ChIP-seq data for multiple histone modifications known to mark cis-regulatory regions. We annotated active and poised promoters and enhancers, as well as regions generally associated with repressed gene expression. We found that poised promoters were associated with neuronal development genes, while active promoters were largely associated with housekeeping genes. Active and poised enhancers were associated with placental development genes, though only active enhancers were associated with genes that have placenta-specific expression. Motif analysis within active enhancers identified a large network of transcription factors, including those that have not been previously studied in the placenta and are candidates for future studies. The data generated and genomic regions annotated provide researchers with a foundation for future studies, aimed at understanding how specific genes in the midgestation mouse placenta are regulated.

Leukemia Inhibitory Factor Induces Proopiomelanocortin via CRH/CRHR Pathway in Mouse Trophoblast

We previously showed that maternal leukemia inhibitory factor (LIF) induces placental production of adrenocorticotropic hormone (ACTH), which stimulates fetal nucleated red blood cells to further secrete LIF and promote neurogenesis in rodent brains. However, the underlying mechanism of LIF-dependent ACTH induction remains unclear. Recently, we found that LIF induces corticotropin-releasing hormone (CRH) in mouse trophoblast stem cells. This finding supports the results of a previous study that CRH, which is produced by the placenta, induces placental ACTH production. In this study, we examined whether the effects of LIF are mediated by the induction of Pomc via CRH upregulation in mouse trophoblast. In vivo, protein levels of LIF and CRH peak in mouse placenta at 13.5 days post coitum. In mouse placenta, Crh mRNA and protein levels significantly increased 3 h after intraperitoneal injection of LIF (5 μg/kg body weight) into dams at 13.5 days post coitum. We also examined the effect of LIF-induced CRH on the expression of Pomc induced by LIF in mouse trophoblast stem cells in vitro. After LIF supplementation for 3 days, we found that the increased expression of Crh-induced by new supplementation of LIF was earlier than that of Pomc. Furthermore, LIF-induced upregulation of Pomc in mouse trophoblast stem cells was attenuated by inhibition of the CRH/CRHR1 pathway, whereas LIF-induced secretion of ACTH was attenuated by inhibition of the JAK/STAT3 pathway. Therefore, LIF indirectly increases placental Pomc expression through the CRH/CRHR1 pathway, and placental ACTH secretion is induced directly by LIF via the JAK/STAT3 pathway.