Scientists have identified a crucial molecular key to healthy embryo implantation and pregnancy in a study that may offer new clues about the medical challenges of infertility/subfertility, abnormal placentation, and placenta previa.
Multi-institutional teams led by researchers at Cincinnati Children's Hospital Medical Center report their results in Cell Reports on July 17. The authors found that uterine expression of a gene called Wnt5a – a major signaling molecule in cell growth and movement in both embryo development and disease – is also critical to healthy embryo implantation in the uterus.
The scientists say that molecular signaling from Wnt5a – working in tandem with its co-receptors ROR1 and ROR2 in the uterus – causes uterine implantation chambers (crypts) in mice to form at regular intervals. The signaling also helps direct embryos to migrate in the proper direction as they settle into the womb. The authors show that disruption of appropriate uterine Wnt5a-ROR signaling leads to abnormal uterine luminal epithelial architecture, crypt formation, disorderly spacing of embryos and implantation. These adverse effects led to defective decidualization, placentation, and ultimately compromised pregnancy outcome.
"Proper implantation is important to healthy pregnancy, and it is not clearly understood what prompts embryos to move and implant within a uterine crypt with regular spacing," said Sudhansu K. Dey, PhD, senior investigator and director of Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center. "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."
Although there are similarities and differences between mouse and human implantation, a role for Wnt5a-ROR signaling in embryo spacing could be clinically relevant, Dey said. This is because the embryo can sometimes implant close to or on the cervix (placenta previa), which can cause extensive bleeding and lead to increased mortality or morbidity for the mother and fetus. Aberrant embryo spacing may also contribute to complications in a multiple gestation pregnancy.
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 two genes (Msx1 and Msx2 - which play integral roles in organ formation during fetal development) are also essential to direct the uterus to the receptive stage for successful embryo implantation. In that study, Dey and colleagues found that Wnt5a signaling is disrupted when Msx is inactivated in the uterus. This suggests that Msx genes have a molecular relationship with Wnt5a. Subsequent studies by Dey and colleagues reported that Msx genes may 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 focuses on the specific molecular and biochemical pathways (and related functions) regulated by Wnt5a-ROR signaling.
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
Journal
Cell Reports