University of Rochester scientists studying a vital protein called Serum Response Factor (SRF) in mice have learned new and unexpected facts about SRF's role in early cardiovascular development, and how a defect in this gene may be an underlying cause in human miscarriages.
The research is reported in this week's Proceedings of the National Academy of Sciences. At this point it is unclear whether subtle defects in SRF might also be linked to adult cardiovascular disease. However, the research provides a foundation for understanding how gene mutations may disrupt heart function, perhaps making some adults more susceptible to heart failure or irregular reactions to drugs.
"One reason for studying the biology of our genetic blueprint is so that we can understand how mutations in the genes encoding for proteins such as SRF may relate to human disease," says Joseph M. Miano, Ph.D., associate professor of Medicine in the Center for Cardiovascular Research at the University's Aab Institute of Biomedical Sciences. "Defining the full spectrum of genetic mutations is key to genetic screening and gene-based therapies."
SRF is one of nature's oldest proteins and is essential for life because it supports the basic internal structure of all living cells. Its function is to carefully turn on 300 of our 30,000 genes. But until now, scientists did not know much about its role in the heart region.
Miano's laboratory led a collaborative study of SRF with investigators from the Medical College of Wisconsin and Johns Hopkins University School of Medicine. They studied mouse embryos, using genetic trickery to nullify SRF in heart cells and key blood vessel cells called smooth muscle cells. They compared the mutant mice to those with a normal amount of SRF in the heart and blood vessels. The heart and related vessels did not develop properly in the mice without SRF, the team discovered.
In fact, while analyzing the heart cells under a high-powered electron microscope, the lab discovered that normal heart cells (with SRF) contained the expected bundles of healthy fibers. Shaped like rubber bands, the bundles work like bands of muscle to keep the heart contracting normally. But in the absence of SRF, the neat bundles were gone. Instead, they were scattered about the heart region, as if the rubber band had been "shredded," Miano says.
Scientists concluded that cells lacking SRF could not sustain life because they lacked the necessary shape, structure and function to stay vital.
"SRF serves a very critical function in directing genes to develop an internal structure that acts sort of like the skeleton in the human body," Miano explains. "You can imagine that without a skeleton, our bodies would flop to the floor. Cells need the same structure and form in order to migrate, contract, and work properly."
Thus, although other scientists have defined hundreds of genes that may cause miscarriages due to cardiovascular defects, the latest research also links SRF for the first time to embryonic heart development. The National Heart, Lung and Blood Institute of the National Institutes of Health funded the research.
Miano's group plans to conduct further studies in mice to pinpoint the exact cause of death among the animals that lack the SRF protein. In addition, the team is searching for all of the genes directed by SRF. The long-tem goal of the research is to provide a foundation for genetic screening for all types of cardiovascular disorders, and perhaps a way to replace the faulty genes through targeted therapy.
Scientists studying a vital protein called Serum Response Factor (SRF) in mice have learned new and unexpected facts about SRF's role in early cardiovascular development, and how a defect in this gene may be an underlying cause in human miscarriages. The research provides a foundation for understanding how gene mutations may disrupt heart function, perhaps making some adults more susceptible to heart failure or irregular reactions to drugs.