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Gene therapy for worms
How a mouse protein rescues a worm’s sensitivity to its environment
To a worm, sugary water is major roadblock. Place a drop in its path, and the worm will sense the change in its environment and swiftly turn tail.
The worm’s reaction is due to an ion channel, identified by scientists at Rockefeller University and the University of California, San Francisco, that may also play a role in the systems that underlie the body’s control of water balance and sense of touch.
The researchers began with a worm that was lacking an ion channel named OSM-9. When a drop of fructose solution is placed in its path, the worm wiggles straight through it — it’s unable to sense the change in osmotic pressure that would cause a non-mutant worm to flee. A worm’s sensitivity to osmotic pressure helps it respond to the saltiness of its environment, a clue that is useful for navigation.
A related protein, called TRPV4, discovered at Rockefeller three years ago, appears to play a similar role in mice to the one OSM-9 plays in worms. Mice born without TRPV4 have difficulty regulating the balance
of salts in their bodies, drink less water than normal, and are unable to sense mechanical stimuli, the researchers
“The mechanism in cells that controls osmotic pressure has been elusive,” says Jeffrey M. Friedman, principal investigator of the studies and the Marilyn M. Simpson Professor and head of the Laboratory of Molecular Genetics at Rockefeller. Friedman’s lab conducted the study in collaboration with Cornelia Bargmann, currently a professor at the University of California, San Francisco, and in whose lab the OSM-9 mutant was discovered in 1997. Both Friedman and Bargmann are Howard Hughes Medical Institute Investigators.
“We now know that TRPV4 is one key protein involved in that process, which may be the most precisely regulated parameter in the body,” Friedman says.
In fact, when the researchers inserted the TRPV4 protein into the OSM-9 deficient worms, the worms regained their lost senses and again dodged the fructose. “When we administered this ‘gene therapy’ to the genetically impaired worms, the results suggested that functions of the defective worm protein and the rat protein are conserved by evolution,” says Wolfgang Liedtke, a research assistant professor in Friedman’s lab and first author of the study. “As a result, the rat protein can replace the function of the missing worm protein.”
The two proteins are not identical; they share only about 25 percent of their amino acid sequence. “That you can rescue the function of a mutated gene with another that has only a one-fourth identity is striking,” Liedtke says.



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