UCSF researcher reports on protein therapy to reverse facial birth defects

February 14, 2000

WASHINGTON, DC -- In the early stages of fetal development, a nudge in the wrong direction can lead to irreparable birth defects, such as major brain and facial deformations. New research from the University of California, San Francisco shows that a brief deprivation of vitamin A in the heads of developing chickens can generate these severe craniofacial deformities, and that dosing the chicken embryo with a regulatory protein can restore a near normal face. The results suggest that, someday, carefully timed protein treatments in human fetuses might repair cleft palate and milder forms of some birth defects.

The research was presented here today (February 18) at the annual meeting of the American Association for the Advancement of Science, by Jill Helms, DDS, PhD, a UCSF professor in the department of orthopedic surgery.

If you're like most people, your face is reasonably symmetrical and everything is more or less in the right place. One series of developmental steps ensures this, and helps form many connections in your brain as well, said Helms. However, a dose of alcohol or carcinogens at the wrong time during development, or a genetic defect, can disturb this process and lead to birth defects such as holoprosencephaly, which affects 1 in 250 fetuses and 1 in 16,000 live births. Fetuses with this condition look as if someone had removed the middle section of the face and compressed the remaining features together.

While pediatric surgeons can repair cleft lip and palate, and fetal surgeons are studying the possibility of repairing more serious defects in the womb, Helms and other biologists are studying a molecular approach to the problem. "The goal is to develop a strategy for treatment of craniofacial defects in utero, or ultimately to prevent these defects in the first place," she said.

To develop such treatments, researchers must first understand the web of different proteins that interact and influence correct face and brain development. Researchers have learned that one central player is the sonic hedgehog protein, which is named after a video game character, and which directs aspects of limb growth and lung development.

Vitamin A, or retinoic acid, is also important -- excess doses during pregnancy, such as from the prescription acne medicine Acutane, can lead to very high incidence of holoprosencephaly and other head and facial defects. Helms and her colleagues discovered a few years ago that these excessive doses of vitamin A suppress sonic hedgehog activity in the embryonic facial tissue.

Since at least some dietary vitamin A is essential for normal fetal development, Helms and her colleagues wanted to study the effects of a vitamin A deficit. They treated developing chicken embryos with a molecule that blocked the vitamin A receptor. After trying several different durations and timings of this treatment, Helms' group found that even a few hours of vitamin A blockage at the right stage of development led to severe holoprosencephaly. "We produced chick embryos that completely lacked a forebrain, and had no middle and upper face. Such conditions are lethal both in humans, and in these chick experiments," she said.

In an attempt to counteract these defects, the researchers dosed the embryos shortly after the inhibition of vitamin A with various proteins involved in regulating face and brain development. They found that strategic doses of sonic hedgehog and another protein called FGF2, restored normal development of the chicks' faces and brains.

"Obviously this is long way from treating a human fetus but it's a very important first step," Helms said.

Before such prenatal treatments are developed, study of these developmental molecules may help doctors to give very early diagnosis of developmental problems, by spotting a critical mutation or low production level of a key protein, Helms said. "We will be able to help parents understand whether the fetus has any life-threatening malformations, and whether they want to terminate a pregnancy if they would have a child with a very severe defect," she said.
-end-


University of California - San Francisco

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.