14 DAY TRIAL // What's the link between our retina and normal child bearing?
A gene!
A gene which is important in impeding cancer emergence on the retina has proven vital in the development of the placenta, the organ connecting the fetus to the maternal body.
When the retinoblastoma (Rb) gene mutates in humans and in mice, it increases the risk of retinoblastoma, a rare eye cancer. Rb was found as the first tumor-suppressor (that protects cells from becoming cancerous) gene, twenty years ago. Its lack of activity has been spotted in many cancers.
When scientists from Ohio State University shut off the gene in mice stem cells that produced the most of the placenta, resulted an abnormal one and miscarriage.
This gene might play an important role in human miscarriages, also. "Our findings strongly suggest that the Rb gene is important in the development of the placenta, but they have other important implications, as well," says principal investigator Gustavo Leone, assistant professor of molecular virology, immunology and medical genetics and a researcher with Ohio State's Comprehensive Cancer Center and human cancer genetics program.
"People born with one mutated Rb gene have a higher risk of developing retinoblastoma. But are they also predisposed to miscarriage? Do Rb-related defects in the placenta cause learning or physical abnormalities? We are investigating these questions now."
The Rb protein plays an important role in regulating the way the cells grow, interacting with 110 other proteins. In 2003, the research team found that the loss of the Rb gene provoked anomalies in the placenta, especially at the contact with the uterus. "This was the first evidence that Rb had an important role in the placenta," says Pamela Wenzel, a graduate student in Leone's laboratory.
Wenzel got mice embryos without a working Rb gene in the placental progenitor cells, which in this case multiplied far too often. Too many cells formed a defective placenta, especially at the contact with the uterus. These embryos died about 15 days after fertilization (the gestation period for mice is 19 days).
The team even managed to produce mice in which the Rb gene was present in the placenta stem cells but absent in cells produced by them. These cells lead to the emergence of a normal placenta and the embryos survived. "This suggests that Rb is important in maintaining placental stems cells, and that it plays a smaller or different role in the cells they give rise to," Leone says.
After that, the team got mice embryos missing both the Rb gene and a second gene, E2f3. The Rb protein interacts in normal conditions with the E2f3 protein. These embryos lived three days longer than the embryos missing Rb only, but in the end, they all died before birth. "This showed that the interaction of these two proteins is definitely important," Leone says.
"It strongly suggests that E2f3 is a key player in mediating Rb function in stem cells and possibly in its role as a tumor suppressor."
The main goal of the team is to see if the Rb gene is behind miscarriages. "Miscarriages have never been linked to a gene defect, but understanding the genetic basis of miscarriage would be a hugely important," Leone says. "It would be the first link between a gene mutation, placental function and development."