Decoding the Mysteries of Development
Our scientists break ground in reproductive biology
Biology books say life begins simply: sperm meets egg. Yet very little else is simple about the early development of human life.
So many things can go wrong at so many stages, it is a wonder any of us make it to birth.
As scientists at Cincinnati Children’s delve deeper into the mysteries of early development, their discoveries could have far-reaching implications for fertility science and understanding the origins of diseases and conditions in children and mothers.
Dey joined Cincinnati Children’s in 2008 to launch the Division of Reproductive Sciences. The Division’s research is part of a major initiative at Cincinnati Children’s to understand and prevent birth defects as well as to combat mortality and life-long health problems related to premature birth.
The Division now has five faculty whose research includes pre-implantation embryo development; the onset of uterine receptivity; implantation; decidualization; placentation; causes of preterm labor as well as epigenetic programming of parental germ cells and mechanism of X-chromosome inactivation by large non-coding RNAs. Faculty members study the implications of signaling pathways in ovarian and uterine cancers as well as the interactions between environmental estrogens and the body.
High stakes research
Premature birth is a major cause of infant mortality worldwide and is an especially serious issue in the United States.
According to a landmark report issued in 2009 from the National Center for Health Statistics, more than 560,000 premature births occur each year in the U.S. In fact, the U.S. ranks 30th in infant mortality, behind most European countries, Canada, Australia, New Zealand, Hong Kong, Singapore, Japan and Israel. Yet much of the research effort to understand the mechanisms of prematurity is still in its infancy.
“We understand very little about the processes of healthy reproduction, but it begins with maternal health. The mechanisms underlying implantation and intrauterine life have long been hidden from us,” says Jeffrey Whitsett, MD,Co-director of the Perinatal Institute. “It is increasingly clear that, although we inherit our genes from our parents, intrauterine growth and development are influenced by many factors that influence the function of our genes that have consequences throughout life. The health of the mother, her nutrition, and environmental exposures may have important impacts on the developing infant. Maternal health is a critical factor for the developing fetus.”
Understanding the mechanisms at work during early development can have long-term, life-long implications, Whitsett says. “Babies that grow poorly in utero can do poorly later in life. They are more likely to develop diabetes, heart disease,and hypertension later in life, and they are more likely to die earlier.”
Understanding implementation
Dey has devoted much of his career to understanding those early developmental mechanisms. His research is focused on pinpointing the molecular landscape that helps prepare the blastocyst for implantation and prepares the uterus to receive it. At Cincinnati Children’s, Dey’s lab has developed mouse models to identify implantation pathways, confirm their function and determine that similar pathways exist in human development.
Successful pregnancy, he has found, depends on many factors moving together in a microscopic dance.
“The embryo must reach the blastocyst stage with primarily two cell types – the inner cell mass and an outer lining called the trophectoderm, later forming the trophoblast, for anchoring into the maternal womb. The blastocyst also must acquire implantation competency,” Dey says.“Meanwhile, the uterine lining must differentiate into a receptive stage. These windows must coincide,” he continues. “Only then can the intense interactions take place to carry out the connections between the blastocyst, trophectoderm and the luminal epithelium of the uterus.”
And all of this happens very quickly.
“This is a very dynamic phase. Things move rapidly,” Dey says. “Even when everything goes perfectly, the window for successful implantation is open only for a short time. If these windows are even slightly out-of-phase, implantation may fail or become abnormal, compromising pregnancy outcome.”
Dey and colleagues have identified several signaling pathways involved in the implantation process. Some seem to function independently; others in cooperation.
“Our mission is to find the major pathways, the places where multiple pathways converge,” Dey says. “These will be the most likely therapeutic targets for assuring successful implantation.”
His key projects include:
• Understanding the role that Cox-2 derived prostaglandins play in female reproduction. Among the findings: a particular molecular signaling network has been found to play a critical role in embryo implantation; described as the cPLA2α-Cox2-PPARδ-Vegf pathway.
• Examining the roles growth factor pathways play in the implantation process. Successful implantation depends, in part, on proper function of a specific signaling network in the uterus – Lif-Hb-Egf-Hoxa10/Msx-Ihh/Bmp/Wnt. Further research has shown that Msx genes, an ancient gene family known for their role in craniofacial and neural crest development, have fundamental functions in uterine biology and implantation in mice.
• Studying the role played by the immunophilin FKbp52, which is critical progesterone receptor activity in the uterus. Deficiency of this factor can result in implantation failure. Studies in mice have shown that the problem can be reversed with high doses of progesterone supplementation.
• Studying the role of cannabinoid/endocannabinoid signaling in pregnancy events. This research has shown that aberrant endocannabinoid signaling is associated with abnormal embryo development and ectopic pregnancy.
In the past year, Dey has added to these understandings with new findings related to the mammalian target of rapamycin 1 (mTORC1) signaling and preterm birth. Details of these findings were recently published in the journal PNAS.
“We have been able to completely rescue preterm birth resulting from heightened mTORC1 signaling in mice,” Dey says.
Influencing pathways
While understanding the mechanisms of implantation can help ensure a successful start to a pregnancy, much research and debate continues about factors that can disrupt the process.
Estrogen and progesterone are the primary forces guiding early development, along with other molecules, Dey says. The optimal balance of these hormones can be disrupted in various ways, ranging from gene defects to external insults such as poor health, bad diet, substance abuse or exposure to toxins.
“Can we influence these pathways? Yes, in some cases,” Dey says.
For example, Cox-2 inhibitors, which help block inflammation in other conditions, can reverse preterm birth in mice. Likewise, rapamycin can correct problems of heightened mTORC1 signaling. The challenge is to move these discoveries from animal models into humans for further evaluation.
“Someday, it may become possible to give a woman a gene screening test before pregnancy and discover her risk factors for unsuccessful implantation,” Dey says. “Based on the results, targeted treatments could be administered to better prepare her.”
How far away might that day be? Dey says translational research will take years to complete.
More to come
In addition to implantation, scientists at the Perinatal Institute study many other aspects of early development.
A new study led by Whitsett and Valérie Besnard, PhD, breaks ground by demonstrating how the mother’s genotype plays a major role in determining the timing of birth. The researchers also found that mothers influence fetal lung growth and maturation — factors crucial to perinatal survival — in more ways than previously understood.
Meanwhile, an ongoing series of experiments led by Alan Jobe, MD, PhD, Director, Division of Perinatal Biology, and Suhas Kallapur, MD, explores how maternal-fetal infections and inflammation can disrupt pregnancy and trigger premature birth.
Previous studies have shown that as many as 60 percent of premature births show evidence of intrauterine infection. New studies are seeking ways to prevent, detect and treat such infections. Better understanding the infection process also is helping define optimal times for delivering infants in high-risk pregnancies.
“Terrible problems can occur if an infant is delivered too prematurely. However, allowing a baby to remain too long in a bad uterine environment also results in terrible problems,” Whitsett says.
Meanwhile, several members of the Perinatal Institute are exploring the maternal-fetal microbiome – the inner universe of bacteria that live in all humans. Early research indicates that maternal diet as well as antibiotic medications can alter this microbiome and potentially influence the course of pregnancy.
Explosive advances in DNA sequencing technology have made it possible to study not just the human genome but also the genetic mix of bacterial strains that lives inside us. In years to come, profiling how the bacterial mix varies among mothers and their developing babies could have far-reaching impact on finding ways to prevent premature birth, Whitsett says.
“This is a very exciting time,” Whitsett says. “These technologies are enabling us to gain insights into uterine biology, implantation and programming of the fetus that were impossible just a few years ago.”
