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Deformed frogs offer genetic clues

February 23, 2001

Mary Ann Travis

A strange phenomenon in Minnesota lakes-an upswing in frogs with extra, missing or deformed limbs-has led to the cloning of a gene in Carol Burdsal's Israel Building lab. A developmental biologist, Burdsal has always been intrigued with how genes regulate the way cells form structures, such as limbs and organs, in embryos.

Now, Burdsal's interest in the deformed frogs has opened up the opportunity to tie her embryologic research to environmental science. And, along the way, her work may help prevent birth defects in human beings.

"The take-home message," says Burdsal, assistant professor of cell and molecular biology, "is that we can clone and characterize genes that can protect embryos from environmental insults, which is what the frogs are suffering right now."

Frogs are "indicator species" for environmental health, says Burdsal. Because they breathe through their skin and live at the interface of air and water, frogs are extremely sensitive to environmental factors. Since increased limb deformities in frogs were first noted in Minnesota lakes in the 1990s, similar frog deformities have been documented in at least 35 other states as well as internationally, says Burdsal.

"Whatever is going on in the water seems to be causing these embryonic abnormalities." A contaminant in the water must be triggering the limb deformities, says Burdsal. From what researchers already know about embryonic limb formation, she says that, more than likely, the problem is a straightforward one-exposure to a Vitamin A-like molecule at the wrong time in the frog's environment.

For most of us, Vitamin A keeps skin healthy and eyes functioning. Vitamin A's chemical name is retinol, and when it goes into a living organism, it is changed into retinal, which is then converted into retinoic acid when it becomes active.

"Retinoic acid is the form of Vitamin A that actually makes things happen inside the cell," says Burdsal. Retinoic acid can go into a cell and turn on genes or cause changes in the expression of genes that is needed for the correct formation of tissues that include the central nervous system, the heart, the eyes and limbs. "If you're exposed at the right time and you have the right levels of retinoic acid during embryogenesis, then development proceeds normally," says Burdsal.

But abnormal exposure can cause birth defects because retinoic acid turns on genes at the wrong time. In Burdsal's lab, she and graduate student Eduardo Martinez-Cabellos have cloned a gene that is essential to detoxifying too much retinoic acid.

The gene is CYP 26, which encodes a protein or enzyme that breaks down or degrades retinoic acid into an inactive form. Burdsal and Martinez-Cabellos have cloned the chick version of the CYP 26 gene, but because limb development is almost identical in all vertebrates their work has broader implications for all vertebrates.

By inserting retinoic acid-soaked beads into chick limb buds, Burdsal and Martinez-Cabellos are investigating CYP 26's role in protecting developing limbs from exposure to abnormally high levels of retinoic acid. Other researchers have simultaneously been working on cloning the CYP 26 gene and their work, along with that of Burdsal and Martinez-Cabellos, suggests that the embryonic expression of CYP 26 may act as a sensor that indicates when an embryo is exposed to too much retinoic acid or a retinoic-acid-like molecule in the environment.

What is original about Burdsal and Martinez-Cabellos' work is that they have observed that CYP 26 is turned on in response to retinoic acid differently at different stages of limb development. They have found that they can use CYP 26 to learn the pattern of differentiation in limb buds and study the signaling of cells in fast-developing embryos.

The formation of specialized structures in the limbs, such as the digits or fingers, is carefully regulated during embryogenesis. At a certain point, Burdsal says, "You reach a stage when the anterior is very different from the posterior." And there's no turning back. This development stage should not be messed with, or abnormalities will occur.

The Centers for Disease Control and Prevention are funding Burdsal's project. The five-year grant, which is in its first year, is part of a larger Tulane/Xavier Center for Bioenvironmental Research grant.

"The way I look at it is that I'm interested in basic developmental biology," says Burdsal, who has taught at Tulane since 1995. "We look at how gene products that are made by the body regulate and influence how organs develop."

The CYP 26 gene work has a "nice tie to environmental effects on development," she says, adding that this work directly applies to humans because "we also may be at risk from retinoid-like molecules in the environment."

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