FRIDAY, Feb. 15, 2002 (HealthDayNews) -- A strain of mice bred with a specific gene mutation could lead to new understandings of congenital heart defects, certain cancers and developmental defects of the brain and spinal cord.
After a year of work, scientists in Georgia report they've created a strain of mice known as "conditional knockouts," meaning the production of a specific gene has been interrupted in a particular organ.
In this case, the researchers have inactivated a gene in the heart called PAX-3, which is believed to play a role in the organ's development. Senior author Simon J. Conway says the findings could translate into new treatments for defects in cardiac development during pregnancy.
The study appears in the February issue of Genesis: The Journal of Genetics and Development.
According to Conway, scientists had already bred mice lacking the PAX-3 gene in all of their cells, but those animals died during gestation. It seems PAX-3, sometimes called the "master control gene," directs many important functions during development.
So researchers had to develop a technique to only knock out PAX-3 in a particular cell type. They accomplished this by breeding mice with genetic "flags" called loxP on either side of the PAX-3 gene.
These mice were then bred with a strain of Cremice. Cre is a bacterial enzyme that targets loxP and chops out whatever genetic material is between the flags.
"It's basically a way of making a mutation, but only in a specific organ or tissue," says Conway, an associate professor at the Medical College of Georgia's Institute of Molecular Medicine and Genetics.
There are roughly 200 strains of Cre, each of which is specific for a certain type of tissue, such as heart or skin.
Conway's laboratory focuses primarily on congenital heart defects. Mutations in PAX-3 cause a defect called common outflow tract, where one rather than two blood vessels leave the heart. Embryos with this defect die in mid-pregnancy.
To determine whether this lack of PAX-3 specifically affects blood vessel formation or pumping of the heart, Conway and his colleagues bred loxP-flagged mice with heart-specific Cre mice, which knocked out the PAX-3 gene only in heart cells.
"If we can work out why this defect occurs in mice, then hopefully we can try and apply that knowledge to what's actually going on in utero to patients that have this particular defect," says Conway.
If they can isolate and cure the defect in mice, says Conway, "that should give us a good clue as to if we're going to be able to try and cure it in utero in the mum, whether it's by gene transfer or pharmacological methods."
Michael D. Collins, an associate professor of environmental health sciences at the University of California, Los Angeles, has studied PAX-3mutations.
"It's known that PAX-3 is important in developing the nervous system, for instance, but it's also very important in muscle development" and other systems, he says. "By being able to separate into tissues, you might be able to separate the different effects of that particular gene."
Collins says the mutant mice could be helpful in understanding two types of a human disorder called Waardenburg syndrome, which is linked to inactivation of the PAX-3 gene. The syndrome causes hearing loss, and changes in skin and hair color.
Mutations in PAX-3 are also linked to the development of certain cancers, including melanoma, and PAX-3-mutant mice that survive gestation could be used to study these diseases, says Conway. The PAX-3 gene is also found in the brain, nerves and neural tube, and the researchers say this technique could be used to study spina bifida.
What To Do: Find out about Waardenburg syndrome from the National Institute on Deafness and Other Communication Disorders, or check out this glossary of genetic terms from the National Human Genome Research Institute.
