Links between glands and implanting embryo

Researchers used 3D imaging with molecular testing to uncover new insight into the earliest stages of mammalian pregnancy-offering clues to unsolved questions in pregnancy. They demonstrate in mice that glands in the uterus must link and communicate directly with the embryo so it will implant and begin pregnancy.

Glands nourish the embryos within the crypt by forging a direct connection between the two entities," says the study's senior investigator, Sudhansu K. Dey, PhD, the director of Reproductive Sciences. "The gland secretions produce molecules essential to embryo development. Without Vangl2, the glands do not extend and connect to the embryo, and the embryo does not properly implant."

The Vangl2 gene is critical to glands extending to the embryo, according to the research team, which included co-first authors Jia Yuan, PhD, and Wenbo Deng, PhD, both members of Dey's laboratory.
The researchers are looking for answers to pregnancy problems to help address high rates of preterm birth and infant mortality, which remain persistent health challenges in modern society.

In their study, researchers produced unprecedented visual and molecular detail about the early stages of a normal mouse pregnancy. They then compared normal mouse pregnancy to malformations that occur in the uterus when the gene Vangl2 is deleted from epithelial cells in the lining of uterine cells and glands. Highly conserved and present across species, the Vangl2 gene produces a protein called Van Gogh-Like Protein 2. The protein helps control collective cell movement and spatial arrangement in developing tissues.

In the normal mouse pregnancy, researchers show that glands providing vital molecular support from the mother to developing embryo extend from the uterine lining and connect directly to the embryo. This connection occurs inside implantation chambers in the uterus called crypts. The study reveals that glands remain connected to embryos through pregnancy's early stages. This is to ensure a competent embryo properly implants in crypts-a critical step to beginning a healthy pregnancy.

After disrupting embryo implantation and pregnancy in the mice, the scientists wanted to uncover the molecular mechanism  that makes glands extend to the embryo and promote implantation. They learned that a growth factor protein called HB-EGF (heparin-binding EGF like growth factor) coordinates with Vangl2 to initiate this process.

HB-EGF is normally expressed in the embryo and crypt. To simulate what occurs in pregnancy, the researchers transferred embryo-sized beads soaked with HB-EGF into the mice uteri. Even in the absence of implanting embryos, the HB-EGF-carrying beads displayed implantation-like responses and showed gland-crypt interaction.

HB-EGF is one of the earliest molecular markers for embryo-uterine interaction in implantation. HB-EGF expression induces genetic activity in the crypt epithelium that collaborates with Vangl2 to direct communication between glands and the implanting embryo. Researchers then tested what happened when they administered HB-EGF to mice with deleted Vangl2.

Genetic deletion caused mice uterine glands to form improperly and wither the implantation chamber. Although the glands connected to the blastocyst, it was insufficient to support implantation. But when researchers administered HB-EGF to the mice, it rescued pregnancy by restoring the crypt and molecular links between the uterine glands and embryo.
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