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Trainor Lab prevents rare birth defect by inactivating p53 gene
Date:2/4/2008

Using a mouse model of Treacher Collins Syndrome (TCS), the Stowers Institutes Trainor Lab has demonstrated that it can prevent this rare disorder of craniofacial development either by inactivating a gene implicated in the abnormality or by inhibiting its protein product.

The work, which was posted to the Web site of the journal Nature Medicine yesterday, is a follow-up to the teams 2006 discovery of the cellular cause of TCS.

The team evaluated how a mutated TCOF1 gene causes the death of neural crest cells that should otherwise form most of the bone, cartilage, and connective tissue that make up the head and face during embryonic development. The loss of these cells results in abnormal development of the ear, nose, and upper and lower jaw, including cleft palate.

The team discovered that chemical inhibition of a single protein, the product of the p53 gene, could prevent the craniofacial abnormalities caused by the TCOF1 mutation. They also showed that inactivation of the p53 gene itself enabled neural crest cells to survive and form normal craniofacial structures in embryos carrying the TCOF1 mutation.

Inhibition of the p53 protein was enough to prevent neural crest cells from dying during early embryogenesis and essentially rescue the mouse embryo from the devastating craniofacial features associated with TCS, said Natalie Jones, Ph.D., formerly a Postdoctoral Research Associate in the Trainor Lab and first author on the paper. The successful rescue of neural crest cell development in a congenital craniofacial anomaly such as TCS is exciting because it provides an attractive model for the prevention of other craniofacial birth defects of similar origins.

These findings are the culmination of years of efforts to better understand TCS, said Paul Trainor, Ph.D., Associate Investigator and senior author on the paper. People diagnosed with severe TCS typically undergo multiple, major reconstructive surgeries tha
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Contact: Marie Jennings
mfj@stowers-institute.org
816-926-4015
Stowers Institute for Medical Research
Source:Eurekalert

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