Cordero used a chemical aptly named cyclopamine to interfere with developmental signals sent by sonic hedgehog, a protein previously implicated in HPE. Although exposure early in development created cyclopic embryos, progressively later exposure mimicked the entire range of symptoms seen in children with HPE. Intriguingly, exposure after sonic hedgehog had already established itself in the divided brain affected only the embryo's face, and holding off just a bit longer resulted in no detectable malformation of either brain or beak.

"We've found that it's possible to recreate the entire spectrum of HPE defects seen in humans by disrupting sonic hedgehog at different times during development," said Helms, "which may explain why some children with HPE are more affected than others."

The scientists believe that HPE may arise from a combination of a faulty sonic hedgehog gene, present from conception, and varying times of exposure to environmental factors that further compromise the protein's signaling. In this scenario, early exposure leads to more severe defects and sometimes death, while later exposure can leave a child with only minor facial abnormalities.

Understanding how brain and facial features are developmentally linked may help doctors at Lucile Packard Children's Hospital and elsewhere hone new therapies or diagnostic procedures for these severe birth defects. "Twenty years ago, physicians didn't understand the mechanisms underlying what they were seeing clinically with HPE and other developmental disorders," said Cordero. "Now with better imaging and molecular diagnostic techniques, we can begin to shed new light on the possible causes of some of these disorders."

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Contact: Krista Conger
kristac@stanford.edu
650-725-5371
Stanford University Medical Center
16-Aug-2004