The amazing uterus
A University of Missouri study reveals how the uterus has glands that not only assist an embryo in implanting into its voluptuous folds, but also extend uterine development throughout pregnancy.
In humans, uterine glands form from the uterine epithelial lining prenatally. In other species, these glands develop after the birth of the animal. In mice, gland development occurs between postnatal day (PND) 5 to PND 7 and involves the Wnt signaling pathways that regulate Lymphoid Enhancing Factor 1. Wnt pathways are proteins that pass signals between cells using cell surface receptors.
For the past several years, scientists and doctors have known glands within the uterus produce Leukemia Inhibitory Factor (LIF), which is vital for embryo implantation and successful pregnancies.
LIF affects cell growth by inhibiting differentiation. When LIF levels drop, a cell differentiates.
Now, researchers at the University of Missouri (MU) find that uterine glands have an additional role in promoting pregnancy beyond producing LIF. This discovery is not only important to understanding how pregnancies develop, but for preventing pregnancy loss and complications such as preeclampsia, according to Thomas Spencer PhD, Professor of Reproductive and Developmental Biology, Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
The study titled: "Forkhead box a2 (FOXA2) is essential for uterine function and fertility," is published in the Proceedings of the National Academy of Sciences (PNAS).
Spencer's team includes the MU Division of Animal Sciences in the College of Agriculture, Food and Natural Resources (CAFNR), Washington State University, and the National Institute of Environmental Health Sciences. They studied development in mice embryos as animal model for humans, and examined blastocyst implantation.
Their observations identify that uterine gland produced FOXA2 regulates Lif. They found this by removing the FOXA2 gene from mouse uteri using common genetic editing techniques. They then administered LIF to mouse moms, replacing what the missing gene could not produce. Pregnacy results were compared with those mice lacking uterine glands altogether.
To their surprise, mice without FOXA2 did not produce LIF, despite having uterine glands. But, after adminstering LIF clinically to these particular mothers, their pregnancies were rescued and carried to term successfully.
However, all mice without uterine glands had failed pregnancies.
"We already knew LIF was vital to ensuring successful pregnancies," Spencer adds. "However, this study has proven that uterine glands serve additional functions for supporting embryo growth and development beyond simply producing LIF.
"Our next step is to determine what additional factors uterine glands produce to support pregnancies. By understanding how these glands work, we can help improve the rates of healthy and successful human and animal pregnancies produced by natural and assisted means."
It appears that uterine gland secretions play an important role not only in blastocyst implantation, but in changes to cells of the endometrium in preparation for and throughout placental growth.
These studies define biological roles for Forkhead box a2 (FOXA2) and glands of the uterus in female reproduction and fertility. FOXA2 is a critical regulator of uterine gland development in the neonate as well as of differentiated gland function in the adult uterus. Our findings provide clear in vivo evidence that FOXA2 regulates uterine expression of Leukemia inhibitory factor (Lif) for blastocyst implantation and that uterine glands play active roles in stromal cell decidualization and placental development. These findings support the idea that pregnancy loss and complications in women may have their origin in uterine gland dysfunction.
Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.
Along with Spencer, the study was authored by Andrew Kelleher and Wang Peng, doctoral students in CAFNR; James Pru and Cindy Pru from Washington State University; and Francesco DeMayo from the National Institute of Environmental Health Sciences.
uterus gland FOXA2 pregnancy LIF
The study, "Forkhead box a2 (FOXA2) is essential for uterine function and fertility," was published in the Proceedings of the National Academy of Sciences (PNAS) doi: 10.1073/pnas/1618433114 and is highlighted "Hunting for Fox(A2): Dual roles in female fertility" in PNAS doi: 10.1073/pnas.1620648114.
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Feb 16, 2017 Fetal Timeline Maternal Timeline News News Archive
The rich blood supply network to the ovaries and uterus is facilitated by uterine glands within
the wall of the uterus — forming from the epithelial lining of the uterus prenatally in humans.
Image Credit:"Textbook of Human Anatomy" written by Henry Gray,
illustrated by Henry Vandyke Carter, 1858.