Growth factors responsible for development, including palate and tooth formation, have more than one way to direct cells to make changes, said Yang Chai (pictured), professor and director of the USC School of Dentistry’s Center for Craniofacial Molecular Biology.
Members of the transforming growth factor beta family, which have been widely studied and have important developmental roles all over the body, work by binding to cell surface receptors and activating signaling molecules within the cell.
The signaling molecules then travel to the nucleus, the cell’s control center, and prompt DNA expression in order to spur changes in the cell.
Chai’s team, which includes fellow researchers Xun Xu, Jun Han, Yoshihiro Ito, and Pablo Bringas Jr., has been specifically scrutinizing growth factor beta’s role in palate formation problems.
Cleft palate is one of the most common congenital birth defects, occurring in one out of every 700 live births, but genes are not the only factor influencing the malformation, he said.
“For instance, we’ve learned that when someone has a haploid insufficiency and is missing one copy of the growth factor beta gene, he or she is more vulnerable to environmental insults that can cause cleft palate, such as drugs, smoking, and alcohol,” Chai said.
Smad4 is one of the main signaling molecules used in the growth factor beta pathway during palate and tooth development. Chai said his team initially had hypothesized that since irregularities in the growth factor beta gene or its cell surface receptors sparked palate malformation in experimental mouse models, knocking out the Smad4 genes would do the same.
“We found that if we blocked growth factor beta or the receptors, a cleft palate develops,” he said. “But when Smad4 was blocked, normal palate epithelium still covered the palatal shelf.”
The team found that p38 MAPK (mitogen activated protein kinase) could take Smad4’s place in the pathway and signal DNA expression to form the palate.
Normally serving as a stress-response protein and activated by environmental insults, such as ultraviolet radiation on skin cells, p38 MAPK appears to act as a “spare tire” when Smad4 function is compromised, Chai said. When either one or the other is inactivated, the palate epithelium will still form properly, failing to form only if both signaling molecules are knocked out.
P38 MAPK isn’t a perfect replacement for Smad4 during oral development – when Smad4 is nonfunctional, teeth only partially form – but the results are still surprising for a molecule better known for its roles during cancer, Chai said.
Further study could have big implications not only on congenital oral birth defects like cleft palate but also on malformations and diseases in tissues throughout the body, and patients could one day be able to take advantage of new genetic counseling and treatment methods stemming from this information, he hopes.
“This information is useful not just for teeth but also for cancer and cell biology in general,” he said. “Ultimately, we have to be translational in order to make ourselves useful to patients.”
Illustration: University of Southern California.
University of Southern California News Release (08/11/08)
Science Daily (08/12/08)
Abstract (Developmental Cell; Vol. 15, Issue 2, 322-329 (08/12/08)