Newly detected communication between two genes involved in embryo implantation shows how some pregnancies fail to get a solid start, according to a reproductive research team at Cincinnati Children’s.

The earliest moments of embryo implantation at the beginning of a pregnancy involve many complex processes that must be executed precisely or the pregnancy can fail. Now reproductive sciences experts at Cincinnati Children’s have discovered another biological process critical to pregnancy success. Detailed findings were published online May 8, 2023, in the journal Proceedings of the National Academy of Sciences (PNAS). The work was led by first author Yeon Sun Kim, PhD, and corresponding authors Xiaofei Sun, PhD, and Sudhansu Dey, PhD.

The team reports detecting vital landing signals being sent between two genes (HB-EGF and Vangl2) as they become expressed in higher concentrations in the uterus before implantation. In mice, HB-EGF expression begins just in the maternal uterus adjacent to the embryo a few hours before the embryo implants. This cell-to-cell communication prompts the lining of the uterus to prepare an implantation chamber, or crypt, to receive the incoming embryo.

When the signaling goes wrong, a malformed crypt results, and the embryo loses its safe place to land. From that point, a poorly attached embryo cannot receive the initial nutrients, blood vessel connections and other support it needs for ongoing growth and development.

Dey’s lab has been studying the role of Vangl2 for several years and has published several studies detailing aspects of its function (see studies in Nature Communications and PNAS). This signaling interaction with HB-EGF had not been discovered until now.

Loading Beads with HB-EGF

Much of the complexity in decoding the steps of early pregnancy comes down to determining which entity is controlling the signal exchange: the mother or the fetus or both. To reduce the variables, the team coated tiny blastocyst-sized beads with HB-EGF proteins. Beads lacking HB-EGF failed to trigger landing preparations in the uterine lining.

These beads made of Sepharose—a polymer material extracted from seaweed—are used in a variety of research and industrial applications. They are blue because the dye itself helps bind with targeted molecules and compounds.

Using the beads eliminated other signals that might have been emitted by an actual embryo, thus allowing the team to confirm the specific role HB-EGF plays during implantation in concert with Vangl2.

“While this study involved mouse models, the human proteome atlas documents the presence of HB-EGF, as well as Vangl2 in the uterus, and HB-EGF is expressed prior to the ‘window of implantation’ in humans,” Dey says. “So this unique dialogue between HB-EGF and Vangl2 may be important to human implantation as well.”

These results suggest potential targets for developing tests to predict the risk of fertility complications and may also lead to treatments for women who carry gene variants that may disrupt embryo implantation. The Dey Lab plans to continue its explorations of other mechanisms at work during the earliest moments of pregnancy.

About the Study

In addition to Kim, Sun and Dey, Cincinnati Children’s co-authors included Jia Yuan, PhD, and Amanda Dewar, MS. The study also included collaborations with experts at Texas A & M University and the Centre de Recherche en Cancérologie in Marseille, France.

Funding sources included grants for the National Institutes of Health (HD103475 and HD068524); and the National Research Foundation of Korea (NRF-2021R1A6A3A03038446). The authors declare no competing interests.