Gene that helps control egg’s journey sheds light on why ectopic pregnancy may occur

Study details the first evidence of gene regulation in the transit of eggs from the ovaries to the uterus in mammals

Ectopic pregnancy is one of the most common prenatal complications, yet the cause of the condition remains unknown. Now researchers at the Wellcome Sanger Institute have pinpointed a gene in mice that plays a key role in the egg’s journey from the ovary to the uterus. When the gene Adgrd1 was deleted, female mice became infertile because the eggs remained stuck in the fallopian tubes.

The study, published today (23 February 2021) in Nature Communications, details the first evidence of gene regulation in the transit of eggs from the ovaries to the uterus in mammals. The findings highlight Adgrd1 as a promising target for future studies in humans, in order to search for genetic mutations or anomalies that may help to explain why ectopic pregnancy occurs.

Each month, a single egg is released from one of a woman’s ovaries and travels to the uterus via the fallopian tubes (also known as oviducts). The egg ‘pauses’ at a certain location, called the ampullary-isthmic junction, for several days. If sperm are present, this is where fertilization occurs. The egg then continues its journey and, if it has been fertilized, will implant into the wall of the uterus. This process is common to many mammal species, including mice.

Ectopic pregnancies occur when a fertilized egg implants and develops outside of the uterus, usually in one of the fallopian tubes. This is known as a tubal pregnancy and it is not possible to save the pregnancy once this occurs*. Ectopic pregnancy affects one to two per cent of all conceptions in the United States and Europe, and is the most common cause of pregnancy-related death in the first trimester.

Movement of the egg is controlled by several factors, including tiny hairs called cilia on the surface of the fallopian tubes which wave the egg towards the uterus, muscle contractions, and the flow of oviductal fluid. But the biology of the egg’s journey is not fully understood, particularly how the ‘pause’ at the ampullary-isthmic junction is regulated.

In this study, researchers at the Wellcome Sanger Institute set out to identify genes required for female fertility whose function was not fully understood. They analysed the International Mouse Phenotyping Consortium database, which contains data on mice that have had certain genes suppressed or ‘switched off’, and identified Adgrd1 as a gene of interest.

When they examined female mice that lacked a functional Adgrd1 gene, they observed that although the mice ovulated normally and fertilisation took place, the eggs could not move past the ampullary-isthmic junction and implanted outside of the uterus**.

To find out why, they investigated the movement of cilia in the fallopian tubes, muscle contractions and the flow of oviductal fluid. Scientists at Genentech, a member of the Roche Group, conducted a genetic screen to determine the molecular mechanisms at play.

The team concluded that the suppression of Adgrd1 activity affected the flow of oviductal fluid, preventing the egg from continuing its journey to the uterus after the ‘pause’ at the ampullary-isthmic junction.

“The flow of oviductal fluid in mammals is somewhat counterintuitive, in that it flows in the opposite direction to the egg’s direction of travel. What we’ve discovered in this study is that the strength of this flow is normally downregulated by the Adgrd1 gene. But when Adgrd1 is suppressed, the flow is not reduced and the egg cannot seem to move past the ampullary-isthmic junction.”

Dr Enrica Bianchi, first author of the study from the Wellcome Sanger Institute

“The molecular cues that dictate G protein-coupled receptor signalling and biological functions still remain poorly understood, despite these proteins represent main drug targets. The identification of Plxdc2 as an activating ligand for Adgrd1 sheds light on the biology of this previously orphan receptor and opens new avenues for the treatment of ectopic pregnancy.”

Nadia Martinez-Martin, a senior author of the paper from biotechnology company Genentech, a member of the Roche Group

Though this study was conducted in mice, a species in which ectopic pregnancy does not occur, the reproductive biology of humans, mice and other mammals share many of the same mechanisms. The next step is to conduct further studies in humans, to see if the role of Adgrd1 is the same and whether mutation or loss of function of this gene correlates with incidence of ectopic pregnancy.

“Though several risk factors of ectopic pregnancy are known, the precise genetic and molecular mechanisms behind the condition have remained unclear. The discovery of the function of Adrgd1 in oviductal fluid regulation, and the consequences of its absence, provides an important clue for researchers studying the causes of ectopic pregnancy in future.”

Dr Gavin Wright, senior author of the study from the Wellcome Sanger Institute

More information

*For more information on ectopic pregnancy, see the NHS website: https://www.nhs.uk/conditions/ectopic-pregnancy/

**Although the mechanism is the same as ectopic pregnancy in humans, the condition does not occur in mice. Rather, the mice are simply infertile.

Publication:

Enrica Bianchi, Yi Sun and Alexandra Almansa-Ordonez et al. (2021). Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit. Nature Communications. DOI: 10.1038/s41467-021-021512-w

https://doi.org/10.1038/s41467-021-21512-w

Funding:

The study was funded by the Medical Research Council and Wellcome.