A Hedgehog's stripes. In a fruit fly embryo, the normal pattern prompted by the Hedgehog pathway (top) is blunted by RNAi, producing a cascade of gene overexpression (bottom).

RNA Interference Roots Out 'Hedgehog' Genes

A technique that blocks specific RNA molecules from producing proteins has let researchers screen thousands of fruit fly genes for involvement in a key cellular signaling cascade. Other scientists say the work, published in today's Science, is as important for its methods as for its results, which help clarify how the so-called Hedgehog pathway guides embryonic development and sometimes causes cancer. This is the first time so-called RNA interference, or RNAi, has been used to successfully screen so many genes.

To ferret out the genes pulling at the pathway's strings, developmental biologists Philip Beachy and Lawrence Lum at Johns Hopkins University School of Medicine in Baltimore and colleagues synthesized double-stranded RNA molecules corresponding to known fruit fly genes. The molecules somehow disable RNAs with a complementary sequence; that stops RNA from transforming genetic signals into proteins. By systematically inhibiting specific RNA molecules and then revving up the Hedgehog pathway, the researchers could see whether a gene was necessary for the pathway to function. (If disrupting a given gene caused cellular or anatomical defects related to abnormal Hedgehog signaling, the researchers knew the gene was a key part of the pathway.)

A trial run on 11 known members of either Hedgehog pathway or a related developmental pathway called Wingless confirmed that the technique accurately picked out Hedgehog genes. When the team applied the technique to 5700 genes, they discovered four that were new to Hedgehog. Injecting Drosophila embryos with RNAi targeting two of those genes left the embryos with serious Hedgehog-related defects, such as improperly arranged body tissues. The researchers suspect that one of these genes is a tumor suppressor that normally blunts the pathway's activity in humans.

Researchers agree that they're only beginning to realize RNAi's power for deciphering complex and overlapping hubs of activity inside cells. "This is a new way to do genetics," says Norbert Perrimon of Harvard Medical School in Boston, who predicts that RNAi will help researchers sketch a more global view of the cell's inner workings.

Related sites
Summary of Philip Beachy's work
Small RNAs as Science's Breakthrough of the Year

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