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New insight into most common forebrain malformation
Date:8/11/2008

ns in an important piece of molecular machinery, the Sonic Hedgehog pathway, a major regulator of fetal brain development.

Thus, the researchers theorized that Six3 might also trigger HPE by compromising the function of the Sonic Hedgehog pathway. For their first experiments, they turned to zebrafish, a widely used animal model for studying genetics and development. Co-authors of the paper from Vanderbilt University used the zebrafish to analyze some of the same defective mutant Six3 genes known to be associated with HPE in humans. They found that the mutations caused partial loss of function of the Six3 gene, an important clue to how the mutations work to cause HPE.

In studies with mice, Oliver and his colleagues found that both Six3 and the Sonic Hedgehog pathway were active at the same time and place in the brain, important evidence that they could work together.

The researchers also developed evidence that the two genes cooperate to cause HPE. Although engineered mice carrying a mutant Six3 gene known to be associated with HPE in humans exhibited only occasional symptoms of HPE, when crossed with mice that also have defects in Sonic Hedgehog, all the animals developed severe HPE.

"This is good evidence for what has been called the 'multi-hit' model of HPE," Oliver said. "In this model it takes mutations in both Six3 and other genes in the Sonic Hedgehog pathway to produce the severe pathology of HPE."

Furthermore, the researchers' molecular studies showed that Six3 and Sonic Hedgehog are intimately involved in regulating normal brain development. Six3 is a significant controller of Sonic Hedgehog; Sonic Hedgehog in turn influences the function of Six3the two working together in a regulatory loop.

The researchers findings about Six3's role offer key insights into HPE, Oliver said. "Sonic Hedgehog is a major player in embryonic development, in the brain as well as elsewhere in the body," Oliver said. "So, thi
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Contact: Carrie Strehlau
media@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

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