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
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,”