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This one is about: Vitamin A / Accutane "Looking for the Causes"

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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."

Copyright 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

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