For expectant couples, finding out they are pregnant is a momentous occasion. While the parents begin preparing for the new arrival, they may not realize that the mom’s body has already successfully completed its own set of preparations. These steps involve signals that pass between pregnancy proteins and the endometrium, or cells that line the uterus, to allow the embryo to successfully implant and continue growing.
According to a research team led by NIEHS scientists, a protein called Gata2, along with the progesterone receptor (PR) — the binding partner of the hormone progesterone — are critical for regulating embryo implantation and the structure of the uterine wall. This work may lead to treatments that help infertile couples, and help women with endometrial cancer and endometriosis, a painful disorder that occurs when uterine-lining tissue grows outside of the uterus. The findings were published online Oct. 25 in Cell Reports.
Proteins working together
The senior NIEHS scientist on the study, Francesco DeMayo, Ph.D., said the name progesterone comes from the phrase "pro-gestational hormone" and indicates its importance in pregnancy. After binding with PR, progesterone is involved in regulating embryo implantation and the ability of the uterus to support the fetus. It also controls the muscles of the uterus, so that the baby is born at the appropriate time.
DeMayo said other scientists found that PR regulated Gata2, so several years ago, when he and his colleagues bred mice that lacked PR, the mice were sterile. In this study, they knocked out Gata2, and again the mice were infertile. It turns out PR and Gata2 have a reciprocal relationship.
"We knew PR regulated Gata2, but we were surprised to find that Gata2 also regulates PR," DeMayo said. "These two genes are so important for pregnancy that they regulate each other to control the crucial stage of embryo implantation."
The data suggest that, to regulate the expression of genes vital for uterine function, both PR and Gata2 must bind to the gene promoter on the DNA at the same time.
Structural changes in the uterine lining
One of the genes PR and Gata2 regulate is the growth factor Indian Hedgehog (Ihh). DeMayo explained that the endometrium is comprised of two types of cells — epithelial and stromal cells. Ihh acts on uterine stromal cells, initiating the preparation for embryo implantation in a process called decidualization.
However, female mice that lack Gata2 exhibit an unusual change in the epithelial cell lining of the uterus. Normally, the uterus is lined with a single layer of epithelial cells, but loss of Gata2 results in the presence of basal cells not commonly found in the uterus. When Gata2 mutant mice were exposed to estrogen, these basal cells expanded, and the uterine epithelium transformed from a single layer of cells to multiple layers of cells. The structural change made the uterus resemble the multilayered vaginal wall. The result indicated that Gata2 protects the uterus from estrogen, whether it comes from the woman’s body or environmental sources, to ensure the uterus can support pregnancy (see graphic).
Carmen Williams, M.D., Ph.D., head of the NIEHS Reproductive Medicine Group, was not involved in the research, but has seen abnormal uterine basal cells before. They are common in mice treated just after birth with diethylstilbestrol (DES), a synthetic estrogen used decades ago to prevent pregnancy complications in American women. Physicians stopped prescribing it after it was linked to the development of vaginal cancer in daughters of mothers who took DES.
"The identification of Gata2 as an important suppressor of basal cells in the uterus is particularly exciting, because we believe these cells progress over time into cancer cells in our mouse model of DES-induced endometrial cancer," Williams said.
Citation: Rubel CA, Wu SP, Lin L, Wang T, Lanz RB, Li X, Kommagani R, Franco HL, Camper SA, Tong Q, Jeong JW, Lydon JP, DeMayo FJ. 2016. A Gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function. Cell Rep 17(5):1414−1425.