A burst of regulatory and protein innovation at the origin of placental mammals drove the emergence of placenta and underpins divergent early pregnancy strategies in modern mammals

Abstract

The origin of placentation in mammals required a symphony of events from protein innovation to the evolution of regulatory networks that could support successful pregnancy from implantation to full gestation. There is variation across mammals in terms of the types of implantation, degree of invasiveness of the trophoblast into the maternal endometrium, and the type of placenta formed. However, there are some signalling networks, e.g. progesterone receptor signalling, that are shared across the clade. We wished to determine what regulates the diverse molecular interactions and morphologies that underpin successful pregnancy in eutheria. Whilst the relationship between miRNAs and pathophysiology of placenta is well established, their role in early implantation and diversity of implantation strategies is not well understood. We identify a cohort of miRNAs that arose coincident with the emergence of placental mammals (mir-127, -185, -188, -28, -324, -331, -340, -378, -423, -433, -505, -542, and -671). We identify 115 genes under positive selection on the stem eutherian lineage and 88 of these are predicted to be regulated by the 13 stem lineage miRNAs. Using two species of mammal that demonstrate the extremes of implantation strategies (invasive and superficial in humans and bovine respectively), we assessed the response of the endometrial epithelium in terms of expression of these miRNAs to early pregnancy molecules. We show that the 13 stem lineage miRNAs are regulated in a species-specific manner. We propose these species-specific regulatory networks contribute to the diversity of pregnancy morphologies observed in eutheria.

MicroRNAs emerging coordinate with placental mammals alter pathways in endometrial epithelia important for endometrial function

“…We tested the hypothesis that a set of miRNAs whose evolutionary appearance coincides with the emergence of placental mammals and were retained in all placental mammal lineages thereafter may play a role in uterine function for successful pregnancy in humans. 18 The rationale for this is the fact that the endometrium and trophoblast have had to co-evolve regulatory signaling networks and the dysregulation of these networks may contribute to pregnancy loss. P4 signaling during the menstrual cycle is critical to establish receptivity of the endometrium to implantation.…”

“… 16 , 17 We have adopted a similar strategy, leading to the identification of 13 miRNA families (17 microRNA genes) that arose coordinate with placental mammals and have been retained in all modern placental mammals. 18 These miRNAs are detectable in the endometrial epithelium and their expression is altered in a species-specific manner by proteins known to facilitate signaling between the embryo and endometrium. 19 , 20 …”

Placental mammal derived microRNAs alter pathways in the endometrial epithelia important for endometrial function

“…We tested the hypothesis that a set of miRNAs whose evolutionary appearance coincides with the emergence of placental mammals and were retained in all placental mammal lineages thereafter may play a role in uterine function for successful pregnancy in humans (18). The rationale for this is the fact that the endometrium and trophoblast have had to co-evolve regulatory signalling networks and the dysregulation of these networks may contribute to pregnancy loss.…”

“…Recent data using an evolutionary approach has identified a key role for the transcription factor, HAND2, and its target genes as important in the pathogenesis of pre-term birth and gestation length (16, 17). We have adopted a similar strategy, leading to the identification of 13 miRNA families (17 microRNA genes) that arose coordinate with placental mammals and have been retained in all modern placental mammals (18). These miRNAs are detectable in the endometrial epithelium and their expression is altered in a species-specific manner by proteins known to facilitate signalling between the embryo and endometrium (19, 20).…”

Live-bearing cockroach genome reveals convergent evolutionary mechanisms linked to viviparity in insects and beyond

“…Moreover, we found that in all viviparous insect branches non-coding RNA processes, involved in the regulation of gene expression (39), are under strengthened selection pressure. Likewise, the basal evolution of eutherian mammals is associated with bursts of regulatory miRNAs regulating the expression of genes involved in placentation (40), non-coding RNA pathways in viviparous insects might therefore play a similar role. In addition, the formation of the placental tissue in mammals is associated with chromosomal maintenance pathways (41), which could explain the strengthened selection pressure of genes involved in chromosomal organisation in viviparous insect branches.…”