Using knockouts and other clever genetic techniques, researchers have scored one success after another in linking mouse genetics to human health. Elaine Fuchs, a researcher at the Rockefeller University, has created a series of mutant mice in which genes related to the protein keratin have been deleted or altered. Almost all these genes involve proteins that are expressed only in the skin and play important roles in the cytoarchitecture of skin cells. Increasingly, these mutant mice are bringing clues to treating various skin diseases in humans.
Sometimes researchers who use mice to investigate unrelated disorders find that their separate discoveries fit extremely well togetherto the benefit of all concerned. Several years ago, for instance, Masashi Yanagisawa, an HHMI investigator at the University of Texas Southwestern Medical Center in Dallas, turned to mice to explore some receptors on the surface of endothelial cells that line blood vessels; these receptors may affect blood pressure and hypertension. But when he created knockouts of one of the receptor genes, he ended up with a distinctively pigmented mousevirtually all white, except for a little tan blaze on the top of its head. He recognized it as a natural mutant that goes by the name of piebalda type of mutant that Shirley Tilghman's group at Princeton used in its research.
At first Yanagisawa could not carry out his research on endothelial biology with these mice because they died within two weeks of birth (the result of an intestinal disorder caused by the same genetic defect). Later on, when he found a way to rescue piebald mice in infancy, he discovered that the adult mutants do have prominent hypertension, as he suspected. But meanwhile he was excited to realize that the gene he had cloned lies at the heart of pigmentation and of a fatal intestinal disorder in humans, Hirschsprung disease, or congenital megacolon, which Tilghman was studying. The knockout mice he had created also failed to develop neurons in the guta major feature of the human disease.
"Of course, we had no idea we were interested in the same gene," says Tilghman, who has worked out her own method of keeping the mice healthy until adulthood and analyzes how the disease develops. "It's a great story for how the interplay between two groups can be very synergistic." It's also a great reminder that the conversations between mouse and man, genetically speaking, will be full of illuminating surprises.
Stephen S. Hall
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Masashi Yanagisawa was surprised to find that he had produced a piebald mouse (center). The white mouse on the left has a similar , but natural, mutation. The darker mouse (right) carries a midler mutation.
Photo: Robert E. Hammer and Masashi Yanagisawa