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.

New exon ignites accelerated evolution of placental gene Nrk in the ancestral lineage of eutherians

Accelerated evolution is often driven by the interaction between environmental factors and genes. However, it remains unclear whether accelerated evolution can be ignited. Here, we focused on adaptive events during the emergence of chorioallantoic placenta. We scanned the chromosome X and identified eight accelerated regions in the ancestral lineage of eutherian mammals. Five of these regions (P = 5.61 × 10−11 ~ 9.03 × 10−8) are located in the five exons of Nik-related kinase (Nrk), which is essential in placenta development and fetoplacental induction of labor. Moreover, a eutherian-specific exogenous exon lack of splice variant was found to be conserved. Structure modelling of NRK suggests that the accelerated exons and the eutherian-specific exon could change the enzymatic activity of eutherian NRK. Since the eutherian-specific exon was surrounded by accelerated exons, it indicates that the accelerated evolution of Nrk may be ignited by the emergence of the new exon in the ancestral lineage of eutherian mammals. The new exon might shift the function of Nrk and provide a new fitness landscape for eutherian species to explore. Although multiple exons were accelerated in both of the Nrk catalytic and regulatory domains, positive selection can only be revealed on the regulatory domain if the branch specific nonsynonymous and synonymous rate test was performed by PAML. Thus, it may be important to detect accelerated evolution when studying positive selection on coding regions. Overall, this work suggests that the fundamental process of placental development and fetoplacental induction of labor has been targeted by positive Darwinian selection. Identifying positively selected placental genes provides insights into how eutherian mammals gain benefits from the invasive chorioallantoic placenta to form one of the most successful groups among terrestrial vertebrates.

Steroids in the establishment and maintenance of pregnancy and at parturition in the mare

Historically, studies on the endocrinology of pregnancy and parturition in horses have made major contributions of relevance to mammals in general. Recent use of liquid chromatography mass spectrometry, measuring multiple steroid hormones simultaneously in blood, foetal and placental tissues throughout normal gestation, and in mares with experimentally induced placentitis, has advanced our current understanding of many of the unusual strategies seen during gestation and at foaling. This includes the stimulation of luteal steroidogeneisis by equine chorionic gonadotropin (eCG) from the endometrial cups, resulting in additional androgen and oestrogen secretion. Progesterone declines as the endometrial cups and eCG disappears, replaced by 5α-dihydroprogesterone (DHP), a potent equine progesterone receptor (PR) agonist, as the chorioallantoic placenta develops. Placental steroidogenesis thereafter is influenced by foetal pregnenolone and dehydroepiandrosterone secretion, providing substrate for 5α-pregnane and oestrogen synthesis, an unusual example of a ‘foeto-placental unit’. Foetal gonadal dehydroepiandrosterone fuels placental oestrone sulphate secretion, peaking at higher concentrations in mares than any other species known, declining steadily thereafter to term. Additional 5α-reduced (DHP) metabolites increase from mid-gestation to peak concentrations 3–5 days before foaling, declining prepartum, most likely as a result of selective loss of placental SRD5A1 (5α-reductase) expression and activity. Similar changes occur in mares with experimentally induced placentitis, which is also associated with a decreased ratio of equine PR-B:PR-A in myometrium, suggesting that progestin withdrawal is both systemic (pregnanes) and local (receptor-dependent) in mares. In addition, some steroids detected during equine pregnancy by immuno-assay are not detected by mass spectrometry, further illustrating the immense value of this technology.

Recent advances in understanding evolution of the placenta: insights from transcriptomics

The mammalian placenta shows an extraordinary degree of variation in gross and fine structure, but this has been difficult to interpret in physiological terms. Transcriptomics offers a path to understanding how structure relates to function. This essay examines how studies of gene transcription can inform us about placental evolution in eutherian and marsupial mammals and more broadly about convergent evolution of viviparity and placentation in vertebrates. Thus far, the focus has been on the chorioallantoic placenta of eutherians at term, the reproductive strategies of eutherians and marsupials, and the decidual response of the uterus at implantation. Future work should address gene expression during early stages of placental development and endeavor to cover all major groups of mammals. Comparative studies across oviparous and viviparous vertebrates have centered on the chorioallantoic membrane and yolk sac. They point to the possibility of defining a set of genes that can be recruited to support commonalities in reproductive strategies. Further advances can be anticipated from single-cell transcriptomics if those techniques are applied to a range of placental structures and in species other than humans and mice.

Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse

Maternal PI3K p110δ has been implicated in smaller litter sizes in mice, but its underlying mechanism remains unclear. The placenta is an indispensable chimeric organ that supports mammalian embryonic development. Using a mouse model of genetic inactivation of PI3K p110δ (p110δD910A/D910A), we show that fetuses carried by p110δD910A/D910A females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110δD910A/D910A females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110δ was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110δ inactivation affected normal TGCs generation and expansion, impeded the branching of chorioallantoic placenta but enhanced the expression of matrix metalloproteinases (MMP-2, MMP-12). Poor vasculature support for the developing fetoplacental unit resulted in fetal death or gross growth retardation. These data, taken together, provide the first in vivo evidence that p110δ may play an important role in placental vascularization through manipulating trophoblast giant cell.

Free blastocyst and implantation stages in the European brown hare: correlation between ultrasound and histological data

The European brown hare (Lepus europaeus) is the only species with superconception, whereby the maternal reproductive tract hosts two sets of conceptuses at different developmental stages. The embryonic development of the hare has not yet been described. To understand the mechanism of superconception, we studied oviduct transport and implantation stages by embryo flushing and live high-resolution ultrasound. Ultrasound data of implantation stages is correlated with histology. In the oviduct, a mucin coat is deposited on the zona pellucida. The blastocysts enter the uterine horns on Day 5, 1 day later than in the rabbit, and directly expand approximately threefold. Spacing is accompanied by peristaltic movement of the endometrium. The mucin coat disappears and the conceptuses attach. The yolk-sac expands in the blastocoel and syncytial knobs invade the antimesometrial endometrium. Maternal blood lacunae appear in the mesometrial endometrial folds, which are subsequently invaded by the syncytiotrophoblast. The haemochorial chorioallantoic placenta forms. The yolk-sac cavity is gradually replaced by the allantois and finally by the exocoel. The different reproductive strategies of the precocial hare and the altricial rabbit are discussed. We assume that the lagomorph-specific mucin coat and the hare-specific delay of the oviduct–uterine transition are prerequisites for superconception.

The murine allantois: a model system for the study of blood vessel formation

The allantois is the embryonic precursor of the umbilical cord in mammals and is one of several embryonic regions, including the yolk sac and dorsal aorta, that undergoes vasculogenesis, the de novo formation of blood vessels. Despite its importance in establishing the chorioallantoic placenta and umbilical circulation, the allantois frequently is overlooked in embryologic studies. Nonetheless, recent studies demonstrate that vasculogenesis, vascular remodeling, and angiogenesis are essential allantois functions in the establishment of the chorioallantoic placenta. Here, we review blood vessel formation in the murine allantois, highlighting the expression of genes and involvement of pathways common to vasculogenesis or angiogenesis in other parts of the embryo. We discuss experimental techniques available for manipulation of the allantois that are unavailable for yolk sac or dorsal aorta, and review how this system has been used as a model system to discover new genes and mechanisms involved in vessel formation. Finally, we discuss the potential of the allantois as a model system to provide insights into disease and therapeutics.