Two Repressor Genes Identified As Essential For Placental Development

April 17, 2012

  • The E2F family of genes is thought to play a crucial role in regulating cell proliferation.

  • It is unclear how these genes carry out their function and interact with one another in intact animals.

  • This study shows that two E2F repressor genes are essential for a functional placenta and for balancing the effect of an E2F activator gene.

COLUMBUS, Ohio – Two particular repressor genes in a family of regulatory genes are vital for controlling cell proliferation during development of the placenta, according to a new study by researchers with the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The two genes are called E2f7 and E2f8. Their absence in stem cells results in a placenta made up of overcrowded and poorly organized cells that cannot properly transport oxygen and nutrients or support normal embryonic development.

When placental stem cells were also missing a third gene, the activating gene called E2f3a, the placental defects were corrected and embryos carried to birth.

The study, published in the journal Developmental Cell, shows at the molecular level how these E2Fs control cell proliferation in intact animals, the researchers say.

"The findings provide insight into the role of these two repressor genes," says principal investigators Gustavo Leone, associate professor of Medicine and associate director of Basic Research at the OSUCCC – James.

The two genes belong to a family of regulatory genes that, in humans, has eight members. They are all believed to activate or suppress other genes to control cell division and proliferation in both normal and cancer cells. But which genes they regulate and how they interact with one another in living animals is poorly understood.

"E2F regulatory genes have been thought to be important for a long time, but with so many of them, it's been hard to tell which one is doing what," Leone says.

"Here, we show that the repressors E2f7 and E2f8 are essential for the development of an intact, functional, placenta, and that they balance out the effects of the activating gene E2f3a," Leone says. "Because these two repressors are important for proliferation, they may also play an important role in suppressing tumor development."

For this study, Leone and his colleagues used animal models that lacked one or more of the three E2F genes in trophoblast stem cells, which give rise to the placenta.

Earlier work led by Leone has shown that in some cases, one E2F gene can be an activator in some tissues and a repressor in others.

Funding from the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, Pelotonia Fellowships, a Pew Charitable Trust Scholar Award and the Leukemia & Lymphoma Society Scholar Award supported this research.

Other Ohio State researchers involved in this study were Madhu M. Ouseph, Jing Li, Hui-Zi Chen, Thierry Pécot, Pamela Wenzel, John C. Thompson, Grant Comstock, Veda Chokshi, Morgan Byrne, Braxton Forde, Jean-Leon Chong, Kun Huang, Raghu Machiraju and Alain de Bruin.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 40 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 210-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by U.S.News & World Report.


A high quality JPEG of Gustavo Leone, PhD, is available here.

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