April 2, 2008
Correcting craniofacial birth defects in utero was once considered one of biology’s most appealing but elusive dreams. The malformations often are triggered early in the first trimester of pregnancy, narrowing the window for prompt diagnosis and possible intervention. In addition to ethical considerations, these conditions typically arise among transient embryonic cell types whose developmental programs are extremely complex and difficult to study. But over the last decade, scientists have steadfastly compiled a list of genes involved in craniofacial development. These leads have allowed more molecular biologists and geneticists to join forces, and these timely collaborations have revealed the first proteins and potential targets to prevent craniofacial birth defects.
In the February issue of the journal Nature Medicine, NIDCR grantees and colleagues take the next step and show in animal studies that molecular targeting can indeed work wonders. They demonstrate that inhibiting the P53 protein in cranial neural crest cells can reverse developing craniofacial birth defects associated with the rare Treacher Collins syndrome. As the scientists explained, people with the condition have mutations in the Tcof1 gene. This leads to inadequate levels of its protein product Treacle in neuroepithelial cells and, in turn, leads to the stabilization of P53, a prominent but relatively short-lived protein. The problem seems to be stabilized P53 increases programmed cell death, or apoptosis, reducing the number of neural crest cells that are essential for normal craniofacial development. The scientists found that by switching off P53 production in mice specially bred to mimic the Treacher Collins syndrome, they could reduce neuroepithelial apoptosis early in development. This restores the normal number of neural crest cells and rescues the normal patterning of the craniofacial structures. The proof of principle work suggests the power of molecular targeting, although more basic research is needed to further explain the result.