Cleft palate has been linked to dozens of genes. While studying one of these genes, researchers at Washington University School of Medicine were surprised to find that cleft palate occurs both when the gene is more active and when it is less active than normal.
The finding suggests this gene, and processes closely associated with it, are central to palate development and could become important targets for investigators seeking nonsurgical treatments to prevent cleft palate before birth, according to the researchers. Their report will appear in an upcoming issue of the Proceedings of the National Academy of Sciences.
"A cleft palate is often diagnosed late in pregnancy and treated surgically after birth. But if we understood the genetic causes of this common birth defect, we might be able to diagnose it much earlier," said senior author David Ornitz, M.D., a professor of developmental biology at the university. "That would potentially allow intervention with prenatal surgery or with drugs or other agents designed to counteract the genetic abnormalities."
Although some cases of cleft lip and palate are linked to environmental factors such as maternal smoking, viral infections, or certain medications, genetic variations play a significant role in many cases. The Washington University researchers studied the fibroblast growth factor receptor 2 (FGFR2) gene, which earlier research implicated in cleft palate.
Mutant proliferation
The researchers focused on mice with Crouzon syndrome, a developmental disorder caused by a mutation in FGFR2. The mutation activates the receptor and results in a syndrome that is characterized by abnormal development of the skull, face, and mouth. It is also associated with an increased incidence of cleft palate.
In effect, the FGFR2 mutation prevents specific growth signals from being switched off. Normally, the signals would be turned on and off in a carefully orchestrated manner to ensure proper patterns of growth and development of embryonic tissues. However, the Crouzon syndrome mutation locks the receptor in a permanently "on" position.
As mouse embryos with the mutation grew, cells destined to become the palate initially grew faster than normal cells, as anticipated. But just before palate formation, the growth of these cells lagged behind their normal pace of proliferation. That was unexpected because the signals created by mutant FGFR2 should logically have maintained an increased rate of cell proliferation in the palate, according to Dr. Ornitz.
In a normal mouse embryo, groups of cells called the palatal shelf on either side of the mouth grow outward, elevate to meet in the middle, and fuse to form the palate. But in the mutant mice embryos, the stunted growth of this tissue prevented the palatal shelves from properly elevating, meeting and fusing. In addition, the researchers detected a decrease in some key components of the supporting matrix between cells of the palate.
Another study co-author, Kai Yu, Ph.D., a scientist in Dr. Ornitz's lab, created genetically engineered mice in which FGF receptors were inactivated in tissue that gives rise to the palate. These mice also developed cleft palate.
In palate cells grown in the lab, the researchers looked at the FGF cell-signaling network, in which FGFR2 participates. They compared the effect of increased activity of FGF signaling with decreased activity of the same network, and interestingly, both led to cleft palate.
"We found that overactivation of an important signaling pathway resulted in loss of function," said lead author Alison Snyder-Warwick, M.D., a plastic surgery resident at Barnes-Jewish Hospital. "Our results suggest a different way of thinking about mutations in the FGF signaling network. This study clearly showed that this FGF signaling pathway is a critical regulator of palate development."
These findings strengthen the evidence that the developmental processes in which FGFR2 is involved could be targeted with drugs to ensure normal palate growth, the researchers concluded.
"It's possible that someday doctors might be able to administer drugs that would either slightly activate or slightly inhibit FGFR2 function," Dr. Ornitz said. "That might be enough to tip the balance from a cleft palate to a normal palate during embryonic development."
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