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

St. Jude Children's Research Hospital scientists have identified one of the molecular mechanisms underlying the genetic brain malformation called holoprosencephaly (HPE). The findings not only yield insights into the most common developmental malformation of the anterior brain and face in newborns, but also help in understanding the intricate process by which the brain forms in the developing fetus.

Led by St. Jude geneticist Guillermo Oliver, Ph.D., the researchers published their findings in the August 11, 2008, issue of the journal Developmental Cell.

"These findings are important, because, while genes that cause HPE have been identified, the interactions among those that produce HPE are not only complex, but poorly understood," Oliver said. "This represents a first step in understanding the mechanism of that interaction."

HPE occurs in about one in every 250 fetuses, frequently causing miscarriage or stillbirth. HPE is present in varying degrees in one in every 16,000 newborns. The disorder is characterized by a failure of the developing brain to separate into right and left hemispheres. Besides brain abnormalities, HPE is characterized by facial malformations such as cleft lip and cleft palate. HPE has been traced to mutations in any of nine genes, although researchers believe the disorder is also influenced by environmental factors such as maternal diabetes, infections during pregnancy or drugs.

In their studies, the researchers sought to understand the role in HPE of a gene that codes for a protein called Six3. In previous studies, Oliver and his colleagues had identified the Six3 protein as critical to fetal brain formation. Also, other studies had implicated defect-causing mutations in Six3 as involved in causing HPE, but they did not know the molecular mechanism by which Six3 promotes HPE.

One clue to Six-3's role in HPE arose from the fact that most of the other HPE-causing genes produce malfunctions 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, this new understanding of its regulation in this very limited time and place in the brain helps us understand at a molecular level some of its overall role in brain formation."

In further studies, the researchers plan to use their understanding of the roles of Six3 and Sonic Hedgehog in HPE to explore why various multi-hit combinations of gene mutations may produce a spectrum of disease from mild to severe.


'/>"/>

Contact: Carrie Strehlau
media@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

Related medicine news :

1. New prion protein discovered by Canadian scientists may offer insight into mad cow disease
2. New insights into common knee injuries
3. SIV infection of natural hosts provides new insights into HIV disease complexity
4. Insight into the struggles of children with language impairments
5. Mothers Blood Could Offer Insights Into Fetal Health
6. Study Offers Insights Into Sensory Perceptions
7. Uncover Key Competitive Intelligence Insights in Webinars Hosted by Best Practices
8. Studies lend insights into colorectal cancer screening
9. Seven Finalists Announced for 2007 Insight Award for Customer Advocacy in Healthcare
10. Influenza: Insights into cell specificity of human vs. avian viruses
11. Genetic approach provides new insight into trastuzumab resistance in breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/23/2017)... ... January 23, 2017 , ... Old School Labs™, makers of the wildly ... Physique bodybuilder Breon Ansley to its growing team of brand ambassadors. The Olympia top ... and in less than a year was able to turn professional, participating in the ...
(Date:1/23/2017)... , ... January 23, 2017 ... ... (SNP) has launched online education programs and resources at seafoodnutrition.org/programs and seafoodnutrition.org/resources ... benefits of a seafood-rich diet. These resources have been developed for use ...
(Date:1/22/2017)... ... , ... Zifam Pinnacle, an Australian company dedicated to providing a unique range ... at the January ECRM Trade Show in Hilton Head, SC. , Zifam Pinnacle develops ... all of its creations to help create a more traditional and natural approach to ...
(Date:1/21/2017)... California (PRWEB) , ... January 21, 2017 , ... "ProDOF is the perfect set of ... subject to another subject in a scene," said Christina Austin - CEO of Pixel Film ... given scene. Easily create the illusion of a DSLR racking focus from one area ...
(Date:1/21/2017)... (PRWEB) , ... January 21, 2017 , ... ... of its new medical office in Petaluma, located at 167 Lynch Creek Way. ... access to SRO sports medicine and rehabilitation services and on-site x-ray ...
Breaking Medicine News(10 mins):
(Date:1/23/2017)... SAN DIEGO and PALMA, ... Laboratoris Sanifit S.L., a clinical-stage biopharmaceutical ... announced that the first patient has been enrolled ... of lead candidate, SNF472, for the treatment of ... haemodialysis (HD). Most ESRD patients, in ...
(Date:1/23/2017)... Jan. 23, 2017 Just two weeks remain until legal experts ... gather in Central London to discuss the flow ... in the market, Parallel Trade 2017 . In the ... of attendees which is available to read in the event download ... Some of ...
(Date:1/21/2017)... ResMed (NYSE: RMD ), BMC ( ... Florida ) today announced they have agreed on a global ... be permitted to sell their existing products in exchange for royalty ... to 3B to close the Florida litigation ... of liability or wrongdoing by any party. The ...
Breaking Medicine Technology: