- What happens after my baby is born?
- What is the placenta? - NHS
- What is the placenta?
- An embryonic invasion
Kalisch-Smith added, "The next part of this project is to see whether nutrient supplementation can reduce or even prevent the adverse effects of alcohol exposure. Periconceptional alcohol exposure causes female-specific perturbations to trophoblast differentiation and placental formation in the rat.
What happens after my baby is born?
Development , , dev Skip to main content Alcohol consumption during pregnancy has been linked to poor growth of the placenta, causing conditions such as fetal growth restriction and low birth weight. The stroma of villi encased in fibrinoid was also positive for tenascin. This glycoprotein was also expressed in the villous stroma directly apposed to cell islands and cell columns. In the proximal portions of both epithelial structures, cytotrophoblast was Ki positive. These data show that tenascin is expressed during the development of the placenta, particularly in the mesenchymal villi, cell islands and cell columns.
These structures are considered to be the proliferating units of the villous trees. In primates, Syncytin-1 was repurposed for the development of a multinucleate tissue layer known as the syncytiotrophoblast, which separates maternal and fetal bloodstreams in the placenta [ 13 ]. Remarkably, Syncytin -like retroviral proteins have been reported to be expressed in the placentas of nearly all mammals, yet Syncytins in different lineages derive from at least 10 independent infections by unrelated retroviruses [ 14 ].
What is the placenta? - NHS
These findings have led to speculation that the co-option of unrelated ERVs in different species was a driving force underlying the evolutionary diversification of the placenta [ 15 ]. Functional studies have revealed that ERV-derived proteins tend to be co-opted for three roles in the placenta: mediating cell—cell fusion to form a multinucleate barrier, suppressing maternal immunity, and protecting the fetus from exogenous viruses [ 12 , 16 ]. However, recent evidence suggests that ERVs may play an even more pervasive role in placenta evolution as noncoding regulatory elements [ 17 ].
The idea that repetitive elements such as ERVs may serve as basic components of gene regulatory networks can be traced back over a half-century to the foundational work of Barbara McClintock, Eric Davidson, and Roy Britten [ 18 , 19 ]. ERVs often include long terminal repeat LTR viral promoter sequences, which can act as cellular promoters or enhancers to modulate the expression of nearby host genes Fig 1A.
The actual contribution of these elements to host gene expression has remained mostly obscure due to their repetitive and noncoding nature, but technological advances such as chromatin immunoprecipitation followed by sequencing ChIP-Seq have helped to cast these elements back into the spotlight.
Large-scale analyses of regulatory elements have revealed that ERVs constitute a surprisingly substantial fraction of cell type-specific regulatory elements in mammalian cells, particularly embryonic stem cells and placental cells [ 20 — 22 ]. A Schematic of an endogenous retrovirus upon integration in the host genome.
B Examples of retrovirus protein-coding [ 13 ] and regulatory sequence [ 24 ] co-option in the placenta. LTR, long terminal repeat. While genomic studies point to ERVs as an abundant source of placenta-specific regulatory elements, their biological relevance to pregnancy remains largely unexplored. Given their retroviral origins, ERVs are not expected to have any benefit for the host, and some may even exhibit pathological activity.
Therefore, without further experimental support, it remains unclear whether ERV-derived regulatory activity is actually relevant for placental function.
The authors originally set out to study the regulation of corticotropin-releasing hormone CRH , which encodes a peptide hormone produced in massive quantities in the human placenta. Placental CRH levels undergo exponential increases throughout gestation, and misregulation of CRH is associated with premature and post-term birth [ 25 ]. Determining how CRH is regulated is important for understanding the molecular control of birth timing but is complicated by the fact that placental expression of CRH is unique to primates.
In all other mammals, CRH is expressed primarily in the hypothalamus and the brain [ 26 ]. The authors hypothesized that placental expression of human CRH is determined by primate-specific regulatory sequence near the gene. Through their examination of the noncoding genomic region surrounding human CRH , they identify a primate-specific ERV insertion located 2 kilobase pairs upstream of the gene. The authors find little transcriptomic evidence for spliced CRH transcripts originating from the ERV, which suggests that the element may act as an enhancer rather than a promoter.
The insertion is an LTR sequence that originates from an ancient retrovirus named transposon-like human element 1B THE1B , which invaded the anthropoid primate lineage approximately 50 million years ago and dispersed roughly 20, elements in the genome before eventually becoming inactivated by mutations. On a genome-wide level, genes located near THE1B-derived LTR elements within 20 kb tend to show placenta-specific expression patterns, suggesting that THE1B elements are an abundant source of placenta-specific enhancers in primate genomes.
Given that placental CRH expression is unique to primates and the THE1B element is a primate-specific ERV, it would seem futile to model the regulation of this locus in mice or any other nonprimate animal. The authors sidestep this obstacle by creating mice with "humanized" placentas, with respect to the CRH locus.
What is the placenta?
Mice typically only show CRH expression in the hypothalamus, but the transgenic mice showed robust and specific expression of human CRH in the hypothalamus and placenta, confirming their usefulness as a model for CRH regulation. Remarkably, mice expressing human CRH in the placenta were born on average 15 hours later that control mice, which coincides with the proposed role for CRH in regulating the timing of human birth.
In this second round of mutants, human CRH was still expressed in the hypothalamus, but its expression in the placenta was eliminated. Strikingly, deletion of the THE1B element fully rescued gestation length back to control levels.
These experiments confirm that the THE1B element functions as a placenta-specific enhancer of CRH and suggest that the co-option of this retroviral element was an important step in the evolution of birth timing in primate pregnancy. Finally, the authors sought to determine the upstream transcription factors responsible for activating THE1B enhancer activity in the placenta. The authors confirm that DLX3 physically interacts with the THE1B element using electrophoretic mobility shift assays and chromatin immunoprecipitation experiments in human placental tissue.
Synthesizing their findings, the authors propose a model where the CRH gene is transcriptionally activated in the placenta through the binding of DLX3 to the THE1B-derived enhancer, which ultimately influences birth timing in pregnancy. The study by Dunn-Fletcher and colleagues demonstrates that ERV LTRs can have biologically significant gene regulatory activities in the placenta and offers a new clue into the molecular basis of human birth timing.
Their findings come with the caveat that the phenotypic effects of CRH expression were observed in transgenic mice, which do not normally express CRH in the placenta. However, without generating transgenic primates, the approach used in this study remains the most practical option for experimentally dissecting primate-specific gene regulation in the placenta.
Several outstanding questions remain.
An embryonic invasion
First, how generally important are ERVs for placental gene expression? There is now strong evidence that ERV-derived proteins play an important role in placental development in many mammals, but whether ERV-derived regulatory elements play similarly significant roles remains unknown. In addition to the enhancer uncovered by this study, ERVs have also contributed a placenta-specific promoter for the human cytochrome P family 19 subfamily A member 1 CYP19 gene and an enhancer for the human major histocompatibility complex , class I , G HLA-G gene [ 27 , 28 ].
Aside from these few examples, the specific effects for most ERV-derived regulatory elements remain largely unknown and require experimental verification. As more potentially regulatory ERVs are experimentally characterized, we will eventually obtain a better understanding of their relative contribution to placenta evolution.
Second, why is ERV transcriptional activity apparently elevated in placental cells? The placenta has long been observed to be a hotbed of ERV expression compared to the embryo, but the reasons for this remain poorly understood [ 29 , 30 ]. One explanation is that placenta-specific activity originally evolved as a parasitic feature of the retrovirus LTR.
Viral expression in the placenta can facilitate maternal—fetal transmission of retroviruses and can theoretically also permit ERVs to invade the germlines of other offspring [ 31 ]. Consequently, ERVs may have repeatedly evolved LTR promoter sequences with strong placenta-specific activity in order to drive their selfish replication. Another possibility is that the unique epigenetic environment of extraembryonic trophoblast cells may be generally more permissive to ERV transcription compared to embryonic cells [ 30 , 32 — 34 ].
Whatever the reason, elevated levels of ERV transcription in the placenta likely facilitated their recurrent co-option for functions in the mammalian placenta. Finally, how do regulatory ERVs influence susceptibility to pregnancy-related complications?
Misexpression of ERV-derived proteins such as Syncytin has been associated with human pregnancy disorders such as pre-eclampsia [ 35 ].