Looking for the Causes
by Elizabeth Zubritsky
As specialists at the UNC-CH craniofacial center study and treat
craniofacial anomalies, another group of researchers is uncovering
the genetic and developmental origins of these birth defects.
Vulnerability During Early
Pregnancy
We're trying to get to the mechanistic level of what causes birth
defects and how to prevent them," says Kathleen Sulik, professor
of cell biology and anatomy. "A lot of times malformations
don't occur in isolation. Defects in seemingly unrelated tissues
can occur in a single individual. What is it that the affected
cells have in common?"
Using pregnant mice, Sulik and her colleagues have investigated
the damaging effects of a number of teratogens, agents which disrupt
embryo development. One of these teratogens is ochratoxin A, often
found on moldy food, especially grains, which is a problem more
common in developing countries than in the U.S. Sulik and her
colleagues have shown that exposing a pregnant mouse to ochratoxin
A on the seventh or eighth day of pregnancy, corresponding to
the third and fourth weeks for humans, causes craniofacial defects
in the embryo, such as cleft lip, midfacial clefting, and exencephaly
(the brain appearing outside the skull).
A second, more notorious group of teratogens is the retinoid family,
which includes vitamin A. Two forms of retinoids are prescribed
as acne treatments-13-cis retinoic acid, an oral medication commonly
known as Accutane, and all-trans retinoic acid, a topical medication
commonly known as Retin A. The severe effects of the oral medication
on developing babies, called retinoic acid embryopathy (RAE),
are well established, but the topical treatment has been considered
safe because the amount absorbed through the skin has been considered
negligible. However, a recent paper by Sulik and her colleagues
demonstrates that low doses of all-trans retinoic acid administered
very early in pregnancy produces some of the craniofacial defects
found in RAE, as well as malformations of the eyes and brain not
previously associated with retinoids. In mice, the critical period
is the seventh day of gestation, which corresponds to the third
week for humans, often before the mother even suspects she is
pregnant.
New Hat for a Neurotransmitter
Jean Lauder, professor of cell biology and anatomy, and the members
of her laboratory have discovered evidence that serotonin, a neurotransmitter
traditionally known to be involved in the regulation of moods
and sleep, plays a crucial part in craniofacial development. Working
with mouse embryos, Lauder's group has discovered that serotonin,
which reaches the embryo via maternal-fetal circulation, helps
to coordinate development of facial structures, including the
eyes, nose, jaw, and teeth. Serotonin is taken up and degraded
by the layer of cells that becomes the skin of the face. This
cycling of serotonin controls its levels in deeper facial tissues,
where receptors for the neurotransmitter help it to regulate growth
and gene expression. Blocking the uptake or degradation of serotonin
or perturbing the receptors results in malformations of facial
structures. "The work says that this neurotransmitter is
also a blood-borne regulator of development," Lauder says.
Deducing the Role of Regulatory
Genes
Thomas Sadler, director of the Birth Defects Center and professor
of cell biology and anatomy, and his colleagues are working with
two genes, Msx1 and Msx2, to figure out why they produce craniofacial
and neural tube (spinal cord) defects. Msx1 and Msx2 are transcription
factors, that is, they promote or inhibit the synthesis of products
from other genes. In the mouse embryo, Msx1 and Msx2 are expressed
in the cells that eventually become the spinal cord and the craniofacial
region. Other researchers have shown that complete loss of Msx1
produces cleft palate and abnormalities in some facial bones,
while complete loss of Msx2 results in premature closure of the
plates in the skull, pushing the brain too far forward. Using
antisense oligonucleotides to inactivate the gene products, Sadler's
group has knocked out both Msx1 and Msx2. When both genes are
disrupted simultaneously, the defects are more severe and occur
more frequently. "We're interested in knowing if we're disrupting
migration or proliferation of cells, or just causing cell death,"
Sadler says. "It doesn't appear that the cells are dying,
but we don't really know how these genes function yet."
©1996 by the University of North Carolina at Chapel Hill in the United States. All rights reserved. No part of this publication may be reproduced without the consent of the University of North Carolina at Chapel Hill.
Last modified: 5/20/96