About the Program

Female reproductive biology is one of the most variable biological characteristics among mammals. With well over 5,000 extant species, this variation represents a largely untapped reservoir of “natural experiments” that can inform all aspects of reproductive biology, especially when animals are different from human, because unexpected observations provoke new questions and can thus lead to new answers. The Section of Molecular Evolution of Reproduction of the Perinatology Research Branch seeks to utilize the store of natural experiments, available among the biodiversity of mammals, for deepening the understanding of human reproductive biology. Various researchers working with the Section have made pioneering contributions to all major themes of female reproductive biology including menstruation, implantation, placentation, cervical remodeling, and parturition.

Objectives

To investigate the evolutionary origin and history of mammalian pregnancy and to utilize this knowledge to further the understanding of the molecular mechanisms underlying human pregnancy.

Research Highlights

Menstruation
Menstruation affects all women of reproductive age, except during periods of pregnancy and lactation. In the West, this means it affects most of the adult life of women, yet we neither know what its functional role is, nor do we know the exact mechanisms causing menstruation. This problem is puzzling because only five percent of placental mammalian species menstruate, showing that mammalian reproduction can happen perfectly well without a menstrual cycle. Yet even more puzzling is the fact that, as researchers at the Section have shown, menstruation evolved at least four times independently among placental mammals[1][see also [2]]. This suggests that the evolution of menstruation is unlikely an “evolutionary accident” but likely arises under specific, but currently unknown, circumstances. This lack of biological context is hampering research into the causes of menstrual disorders. However, the recent discovery of a menstruating rodent, spiny mouse Acomys caharinus, raises the possibility to investigate the origin and thus the biological function of menstruation with experimentally accessible species.

1. The Evolution of Menstruation in Mammals

Implantation
Embryo implantation is a distinguishing characteristic of placental mammals. Unlike all other life bearing animals, the embryo of most placental mammals becomes embedded in the maternal tissue of the uterus in a process that resembles an inflammation. This raises both an evolutionary mystery as well as a clinical problem. The clinical problem is this: why is the process of embryo implantation associated with inflammatory processes, while for most of the pregnancy inflammation is the greatest threat for the continuation of pregnancy? Researchers at the Section called this the “inflammation paradox”[3]. From the evolutionary point of view, implantation is also paradoxical. How can an embryo evolve to invade maternal tissue if the wound caused by the embryo inevitably has to lead to inflammation and thus risks the destruction of the embryo? The solution came from a study by researchers at the Section on the fetal maternal relationship in the opossum, which is not a placental mammal and a model for the mode of reproduction before the origin of placental mammals[4]. It has been found that in the opossum embryo attachment also leads to inflammation, but this inflammation is progressive and ends in parturition. It was thus hypothesized that the key innovation that allowed the extended gestation in placental mammals was a process that suppressed the inflammatory attachment reaction. Specifically, it was show in a recent paper that the decidual cell plays a critical role in this innovation in preventing the recruitment of neutrophils[5]. These findings imply that the activation of the innate immune system early in pregnancy is a natural part of the early phase of pregnancy while only the later stages require active suppression of inflammation in the uterus. This model has important implications for the role anti-inflammatory treatments can play in different phases of pregnancy.

2. The evolution of implantation.

3. Phylogenetic analysis of inflammation during implantation.

4. The expression of inflammatory mediators during implantation: a comparison of the armadillo and hyrax.

Placentation
For most of the history of reproductive biology the non-invasive placenta of cows, horses and other farm animals was considered a primitive feature, whereas the deeply invasive placenta of humans was considered the most advanced form. In 2006 a paradigm shifting PNAS paper out of the Section has shown that this scenario is wrong [6]. This work has caused a revolution in our understanding of placentation. Now it is broadly accepted that the first placental mammals had a deeply invasive placentation while the situation in farm animals is secondarily evolved. One consequence of this insight is that differences in placental morphology and function are not the result of a steady march towards more efficient placental physiology, but represent different resolutions, in different lineages, of the fetal-maternal conflict over the control of nutrient availability.
Cervical Ripening and Parturition
The regulation of cervical ripening in preparation for birth is critical for determining the timing of birth. Early cervical ripening is also a risk factor for premature birth, but its mechanisms are not well understood. To address this gap in our knowledge, researcher at the Section have used a comparative study of cervical gene expression of mammals and identified a novel aspect associated with cervical ripening, the regulation of histone acetylation[7]. This discovery is interesting because drugs that affect histone acetylation are a well-established tool in the arsenal of clinical medicine and is thus an easy therapeutic target to implement. Researchers at the Section are currently conducting animal experiments exploring whether pharmacological regulation of histone acetylation can influence cervical ripening.