Researchers find key to Sonic hedgehog control of brain development

Oct 28, 2008
Comparison of expression of a reporter gene under the regulatory control of a wild type and mutant Shh brain enhancer - SBE2 (blue). Note that the reporter gene is expressed more fully from the wild type (WT) versus the mutant (Mut) Shh enhancer in the hypothalamus of a 10-day-old mouse embryo. Credit: Douglas J. Epstein, University of Pennsylvania School of Medicine

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 sequences that drive a gene's transcription, ensuring that it is turned on and off at the appropriate time. Enhancers can be located nearby to the genes they regulate or, as in the case of Shh, operate over hundreds of thousands of base pairs away.

In the current study, the investigators searched for mutations in the enhancer sequence in holoprosencephalic patients. They identified one mutation in a region of the enhancer that has been conserved for over 300 million years of evolution, attesting to the importance of these sequences. The mutation caused a significant reduction in Shh enhancer activity in the hypothalamus.

In turn, they screened for proteins that assemble on the Shh brain enhancer. They found a protein called Six3 that binds less tightly to the mutated form of the Shh enhancer. The enhancer can't work without the proteins that bind to it, and this study showed a direct link between the Six3 DNA- binding protein, the sequence that regulates Shh, and hence brain development. Interestingly, mutations in Six3 also cause holoprosencephaly, but the mechanism by which this occurs was previously unknown. Results from the Penn study now indicate that it is likely through the failure to activate Shh.

Identifyng additional components of the Shh brain enhancer complex will further our understanding of how gene regulatory networks operate during normal brain development. This type of basic research should also be instrumental in identifying additional causes of holoprosencephaly and other congenital brain anomalies resulting from the misregulation of Shh expression.

Source: University of Pennsylvania

Explore further: First genetic link discovered to difficult-to-diagnose breast cancer sub-type

add to favorites email to friend print save as pdf

Related Stories

Recommended for you

Refining the language for chromosomes

Apr 17, 2014

When talking about genetic abnormalities at the DNA level that occur when chromosomes swap, delete or add parts, there is an evolving communication gap both in the science and medical worlds, leading to inconsistencies in ...

Down's chromosome cause genome-wide disruption

Apr 16, 2014

The extra copy of Chromosome 21 that causes Down's syndrome throws a spanner into the workings of all the other chromosomes as well, said a study published Wednesday that surprised its authors.

User comments : 0

More news stories

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Study says we're over the hill at 24

(Medical Xpress)—It's a hard pill to swallow, but if you're over 24 years of age you've already reached your peak in terms of your cognitive motor performance, according to a new Simon Fraser University study.

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.