At the California Institute of Technology in Pasadena, HHMI investigator Paul Sternberg recently found another connection between the social behavior of worms and human diseases. Sternberg has a long-standing interest in genes that control the development of sexual organs in C. elegans. This subject has brought him many unexpected rewards, from major findings about a cancer gene to the recent discovery of a genetic mutation that holds clues to human kidney disease.
At first, while working in Robert Horvitz's lab in the 1980s, Sternberg focused on hermaphrodite worms. These worms have a vulva and are really females, but they also produce some sperm, with which they fertilize their first batch of eggs internally. (From then on, they mostly receive sperm from males, thereby gaining additional chances to produce offspring.)
Some mutant hermaphrodites fail to develop a vulva. After self-fertilizing their eggs, they have no way of laying them. The eggs then hatch inside the worms' bodies and the larvae proceed to devour their mothers.
Sternberg and Horvitz discovered three genes that were involved in this error. To their amazement, they found that one of these genes belonged to the notorious RAS family of proto-oncogenesgenes which, when mutated, can cause cancer. Mutant RAS genes were originally identified in human cancers of the colon, liver, lungs, and bladder, as well as in some leukemias, but researchers had no idea what RAS does or what pathway it acts through.
The answers came from the discovery that the RAS genes in human tumors contain the same mutation that prevented the worms from developing a vulva. The human RAS mutation was also strikingly similar to a mutation that prevented the normal development of the fruit fly eye.
Sternberg then began to study C. elegans males, which are considerably smaller than the hermaphrodites. Normally, when a male worm encounters a hermaphrodite, he approaches her, places his tail, which contains sensory structures, flush with the hermaphrodite, and glides along her body until he locates her vulva. Then he inserts two spicules into the vulva to steady himself and transfers his sperm.
While looking for the genes that control each step in this elaborate routine, Sternberg and his colleague Maureen Barr encountered males that acted strangely in the presence of hermaphrodites. Barr noticed that some of these male worms glided right past the hermaphrodites' vulvas, as if unaware of their presence. The researchers then identified the gene that was responsible for this unusual behavior and called it lov-1 (for location of vulva). They proved its function by showing that if they injected a normal copy of the gene into mutant male worms, the worms found the vulva without difficulty and mated normally.
When the researchers ran the DNA sequence of lov-1 through various gene databases, however, they could hardly believe what they found: lov-1 closely matched PKD1, a human gene known to be involved in polycystic kidney disease.
"This was a surprise intersection of two different areas," Sternberg says. Though polycystic kidney disease is a fairly common hereditary disorder, it remains poorly understood. Scientists know that a defect in PKD1 causes the formation of cysts in the kidney and that this potentially fatal condition affects more than 12 million people worldwide. But they have not been able to figure out what PKD1 does normally, how the mutation leads to cysts, or how the disease might be treated.
"The advantage of working with C. elegans is that we can do a lot of experiments much faster than in mammalian cells," Sternberg says. "It would be exciting to find more genes that work with lov-1 in the worm, since those genes may also work together in the kidney."
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Paul Sternberg sorts slides showing the odd behavior of sexually incompetent worms...
Photo: Kay Chernush
In normal mating, the male stops at the hermaphrodite's vulva and prepares to insert his spicules into it so he can transfer his sperm.
Image: Katharine S. Liu and Paul W. Sternberg, Neuron, vol. 14, No. 1, cover, January 1995 ©1995 by Cell Press