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Penn researchers find key to Sonic hedgehog control of brain development
Date:10/28/2008

PHILADELPHIA University of Pennsylvania School of Medicine researchers have discovered how the expression of the Sonic hedgehog gene is regulated during brain development and how mutations that alter this process cause brain malformations. The results appear online this month in Nature Genetics.

Sonic hedgehog (Shh) plays a key role in regulating many aspects of embryonic development including, growth of digits on limbs and organization of neurons in the brain. It controls cell division of adult stem cells and has been implicated in some cancers.

"Elucidating the regulators of Shh expression in the forebrain will not only improve our fundamental understanding of brain development, but may also lead to novel insights into the pathogenesis of holoprosencephaly and possibly other malformations in the brain," says senior author Douglas J. Epstein, PhD, Associate Professor of Genetics.

Holoprosencephaly occurs when an embryo's forebrain, the large frontal area of the human brain, fails to divide to form left and right halves, causing defects in the development of the face and in brain structure and function. Symptoms can be moderate, in the case of a cleft lip or palate to severe, as in cyclopia, the development of one eye rather than two. About one in 16,000 live births display a type of holoprosencephaly.

A decrease in the Shh protein by 50 percent predisposes humans to craniofacial problems such as holoprosencephaly. Too much Shh can lead to tumor formation. Shh is the most commonly mutated gene in holoprosencephaly and can involve about seven other genes.

In a previous study published in the journal Development, the Penn group surveyed one million bases, the basic building blocks of DNA, in transgenic mice for the sequences that turn on Shh during the development of the forebrain. They identified a brain specific enhancer that drives expression of Shh in the hypothalamus. Enhancers are regulatory sequence
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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