Why were these mice, all of whom lacked a gene called Hoxb8, so driven to groom themselves? "We initially thought they may have an itch," says Capecchi, an HHMI investigator who studied these animals with Greer. "We looked very carefully at their skin and all sensory inputs to the skin—sensitivity to pressure, temperature, pain, etc. Was there an irritation? An allergic response? We even gave them grafts of normal skin, but that didn't reduce the obsessive grooming. The skin appeared perfectly normal."

The researchers then set up infrared cameras to record what the mice did by night, when they are most active, as well as by day. Each mouse cage held a normal and a mutant mouse. After analyzing 24 hours of videotape, the researchers concluded that the mutant mice acted normally in almost every way. They ate, drank, climbed, hung upside down from the roof of the cage and built nests at the same rate as their normal counterparts. However, they spent nearly twice as much time licking and biting their bodies. They also groomed their cage mates. All this activity kept them so busy that they slept about one hour less each day than the normal mice.

Intrigued, the researchers wondered whether the missing Hoxb8 gene—one of 39 homeobox-containing (Hox) genes that play major roles in the early development of the body and brain—is normally expressed in the central nervous system of adult mice. They found that it is, and apparently, the protein produced by this single gene is required to prevent mice from compulsively grooming their bodies.

Because mouse genes are nearly identical to ours, Capecchi points out, this research very likely applies to humans as well. Thus his lab has become interested in people who suffer from trichotillomania—a condition in which people cannot stop pulling their hair out. As one patient reported to the Trichotillomania Learning Center, in Santa Cruz, California, "Talking on the phone for more than five minutes usually means that I won't have eyebrows or lashes when I hang up."

About 6 million Americans are estimated to have trichotillomania. What especially interests Capecchi is that identical twins share this trait 95 percent of the time and that it runs in families, suggesting some sort of genetic component. Could these people be suffering from a defect in Hoxb8?

Capecchi is determined to find out. He is collecting blood samples from approximately 150 patients in Utah and is planning to collect more samples nationwide. "We'll sequence the Hox genes from each patient," he says. "Besides Hoxb8, two other Hox genes may be involved. Obviously, if these genes are mutated in patients, we may find new targets for therapy."

If this project works out, other kinds of obsessive-compulsive disorders may benefit from studies of mouse genes. "Obsessive-compulsive disorders are associated with repetitive functions, such as washing one's hands over and over again until the skin rubs off, or lining up one's shoes over and over," Capecchi says. "We're going to look for displays of repetitive behavior in mice." It won't be easy, he admits. "Perhaps we'll give them some things to play with and see if they line them up. There are lots of subtle nuances to mouse behavior, and we'll have to keep our minds open. We're just beginning our analysis of what the Hox genes are doing in the adult brain."

—Maya Pines

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Reprinted from the HHMI Bulletin,
June 2002, page 36.
©2002 Howard Hughes Medical Institute