Development of method to study the function of genes that trigger new limb growth in salamanders may yield clues for potential human therapies
Irvine, Calif., Feb. 10, 2000 — Researchers at UC Irvine have developed an effective method of studying the function of the specific genes necessary for limb regeneration in salamanders, a finding that may ultimately provide key information leading to new approaches for the treatment of such ailments as spinal cord injury, deep wounds and burns.
This discovery allows researchers for the first time to isolate and study cell activity at the site of regeneration in this amphibian animal, the only vertebrate life form that can grow back lost limbs. Susan V. Bryant, David M. Gardiner and Stιphane Roy of UCI's Department of Developmental and Cell Biology found that by using a laboratory-altered version of a cowpox virus-called a vaccinia virus-as a carrier, they were able to introduce molecules into the cells where regeneration occurs and initiate specific gene functions. Their findings appear in the Feb. 15 issue of Developmental Biology.
Although salamander studies have yielded much information on how limbs regenerate, researchers had been limited in their ability to analyze the function of the specific genes necessary for regeneration. By understanding the process of regeneration, researchers may ultimately find new approaches and therapies for replacing and repairing damaged or diseased parts of the human body.
"Before, we were in the dark trying to understand the function of genes in regeneration," Bryant said. "By understanding which genes do what in limb regeneration, it will allow us to look at why animals can't regenerate, and it puts us on the path to design ways to stimulate regeneration where it never existed before."
Mice, frogs and chicks also are used in regeneration research, although these vertebrates do not have the natural ability of the salamander to grow back lost limbs. The challenge with the UCI salamander research, Bryant said, was finding an effective viral carrier. Viruses tested before vaccinia did not infect the targeted cells, making it impossible to introduce specific molecules for analysis.
In one key test in their latest study, the UCI researchers developed a vaccinia virus with the ability to secrete a specific protein that helps initiate the cell activity leading to tissue growth. The virus secreting this molecule-a protein called sonic hedgehog (Shh)-was injected into cells at the limb amputation site during different stages of regeneration.
In testing the function of Shh in these cells, researchers learned more about the role this protein plays in the regeneration process. During the first phase of limb growth, no Shh activity was detected. But in later stages, Shh molecules were observed secreting from genes in the regenerating cells and triggering new cell growth and limb development. Through this, researchers learned Shh plays the same role in salamander limb regeneration as it does in the development of other vertebrates, providing clues on how this protein may function in the human body.
The UCI researchers are continuing with vaccinia virus research, testing other molecules to analyze the function of genes in regeneration. Specifically, they will be studying gene activity during the initial phases of limb regeneration. Eventually, the researchers plan to produce a database detailing the specific activity of each gene involved in the regeneration process.
Bryant, Gardiner and Roy conduct their research through UCI's Developmental Biology Center. This vaccinia project was funded by a grant from the National Institutes of Health.
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