Gene discovery may prevent craniofacial birth defects

Craniofacial researchers have developed an animal model that explains how skull malformations occur and how they might be prevented.

Birth defects of the face and skull are relatively common in humans, striking one in 500 to 1,000 babies. Defects can include cleft lip or palate, congenitally missing teeth and severe malformations of the skull.

A group led by Yang Chai, chair of the division of craniofacial sciences and therapeutics in the USC School of Dentistry, has identified the genetic factor leading to malformation of the forehead and frontal part of the skull. The discovery was published online Dec. 20 by the journal Development.

Children with frontal bone defects lack vital protection for their brain. They also may develop bulging, irregularly shaped heads.

Chai's group focused on a gene called transforming growth factor- beta. TGF-beta is known to play an important role in human and animal development.

To study the gene's effect on the skull, the researchers deleted TGF-beta in mice embryos, but only in the cranial neural crest cells that build facial bone and cartilage.

"If you knock out this gene in every single cell in the body, the embryos die very early. That doesn't help us figure out the role the gene plays in cranial development," Chai said.

The rest of the embryo's cells were allowed to retain the gene and grew normally.

Mice born from the treated embryos carried severe craniofacial defects, including cleft palate and skull malformations.

The results showed that TGF-beta is necessary for proper development of frontal bones.

In addition, the researchers found that they could rehabilitate embryos with missing TGF-beta by inoculating them with FGF, an intermediate protein in the "signaling cascade" that starts with TGF-beta and ends with healthy facial structures.

Chai's group concluded that TGF-beta acts through FGF to ensure proper development. This suggests a potential therapy for embryos that are missing TGF-beta in the neural crest cells.

"This might be useful to try out some possible rescue experiments," Chai said.

Although Chai's current results apply only to mice, a paper last spring in Nature Genetics (Loeys et al., 2005) identified a handful of human families with inherited mutations in TGF-beta receptors and with a high incidence of craniofacial defects, including cleft palate and skull malformations.

If the signaling mechanism in mice were to carry over to humans, pharmaceutical researchers could start to investigate FGF as a potential supplement for pregnant women, analogous to folic acid for prevention of spina bifida.

Chai noted that the FGF supplements in mice restored normal cell growth only in the skull region.