Key to egg implantation in uterus
Scientists have identified a crucial regulator for how an egg correctly implants. Wnt5a may also help explain the mechanical defects affecting infertility, abnormal placental development and placenta previa.
Multi-institutional teams led by researchers at Cincinnati Children's Hospital Medical Center have found that Wnt5a — a major signaling molecule for cell growth and movement in embryos (and disease) — is also critical to healthy embryo implantation in the uterus.
Research results are published in the journal Cell Reports.
The scientists believe that molecular signaling from Wnt5a – along with its co-receptors ROR1 and ROR2 in the uterus – stimulates uterine implantation chambers (known as "crypts") to form at regular intervals in mice allowing for multiple pup embryos to implant. Wnt5a signaling also helps direct embryos to move in the right direction toward the crypt.
Researchers show that disrupting Wnt5a-ROR signaling leads to an abnormal uterine architecture, resulting in bad crypt formation, disorder in the spacing of multiple embryos and errors in implantation. These adverse effects ultimately compromise pregnancy outcomes for mother and child.
"Proper implantation is important to healthy pregnancy, and it is not clearly understood what prompts embryos to move and implant within a uterine crypt. If something goes wrong at this stage, there could be adverse effects throughout the course of pregnancy – whether it is subfertility, infertility, restricted growth, miscarriage or preterm birth,"says Sudhansu K. Dey, PhD, senior investigator, and director of the Division of Reproductive Sciences at the Cincinnati Children's Hospital Medical Center.
Wnt5a-ROR signaling in embryo spacing could be clinically relevant for humans.
Particularly if the embryo implants close to or on the cervix as in placenta previa, which can cause extensive bleeding and lead to increased chance for death of the mother and fetus.
Aberrant embryo spacing due to Wnt5a signally errors, may also contribute to complications in multiple birth pregnancies.
The current study is a continuation of the work Dey and his team published in 2011 in Developmental Cell. Also conducted in mice, this study showed that two genes — Msx1 and Msx2 — play integral roles in organ formation during fetal development and are essential to directing the uterus to be receptive for successful embryo implantation.
In their previous study, Dey and colleagues found Wnt5a signaling is disrupted when Msx is inactive in the uterus. This suggests that Msx genes have a molecular relationship with Wnt5a. Subsequent studies by Dey and colleagues reported Msx genes may also be critical for successful implantation in other mammalian species.
Now that the researchers have identified Wnt5a and ROR as key regulators in embryo spacing and implantation, their next study will focus on the specific molecular and biochemical pathways and related functions regulated by Wnt5a-ROR signaling.
•Normal embryo implantation requires regulated uterine Wnt5a-ROR signaling
•Wnt5a-ROR signaling aids in orienting villi-like epithelial projections
•Aberrant Wnt5a-ROR signaling is reflected in altered Bmp2-Smad signaling
•Defective implantation compromises decidualization, placentation, and fertility
Embryo homing and implantation occur within a crypt (implantation chamber) at the antimesometrial (AM) pole along the uterus. The mechanism by which this is achieved is not known. Here, we show that villi-like epithelial projections from the main uterine lumen toward the AM pole at regularly spaced intervals, that form crypts for embryo implantation, were disrupted in mice with uterine loss or gain of function of Wnt5a, or loss of function of both Ror1 and Ror2. This disruption of Wnt5a-ROR signaling resulted in disorderly epithelial projections, crypt formation, embryo spacing, and impaired implantation. These early disturbances under abnormal Wnt5a-ROR signaling were reflected in adverse late pregnancy events, including defective decidualization and placentation, ultimately leading to compromised pregnancy outcomes. This study presents deeper insight regarding the formation of organized epithelial projections for crypt formation and embryo implantation for pregnancy success.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Jeeyeon Cha, an MD/PhD student in Dey's lab, is the first author on the Cell Reports Paper. Other co-authors include Amanda Bartos, Craig Park, Xiaofei Sun, and Yingju Li in Dey's lab; and Sang-Wook Cha in the Division of Developmental Biology. This study was conducted in collaboration with Rieko Ajima, National Institute of Genetics in Japan; Henry Ho, Department of Cell Biology and Human Anatomy, UC Davis; and Terry Yamaguchi, National Cancer Institute (National Institutes of Health).
Funding support for the study came in part from the National Institutes of Health, the March of Dimes, an individual National Research Service Award (F30AG040858), and a Lalor Foundation Post-doctoral Fellowship.
About Cincinnati Children's:
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S.News and World Report's 2014 Best Children's Hospitals. It is also ranked in the top 10 for all 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter
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