Yuh Nung Jan, Lily Jan, and postdoc Chay Kuo hopes that a tissue repair mechanism they found in mice exists in humans.

He set out to create a strain of mice in which he could control when the genes were inactivated in the SVZ's stem cells. After 3 years' work, Kuo bred the colony that made possible the experiments that led to the brain-repair discovery.

Sitting at his office computer, Yuh Nung Jan pulls up slides of magnified purple-stained slices of mouse brain from Kuo's mutants. One image, from a 2-week-old pup, shows a triangular hole—a grossly enlarged lateral ventricle. But in another slide, from a 6-week-old, the gap has shrunk to near normal. Moreover, these mutants, which start out smaller than control mice, catch up in growth and seem to be just fine.

Numb and Numblike do more than control neural stem-cell specialization, Jan says. The mouse analyses indicate that these genes also act to maintain junctions between epithelial cells that line the ventricle wall. In mutants without the genes, he says, "the wall sort of disintegrates."

Then, because some SVZ stem cells escape the gene knockout treatment, says Kuo, those cells are able to trigger the rebuilding of the wall—although it is not the same as the original—and save the animals.

The investigators are now exploring the cellular underpinnings of the lateral-ventricle repair; they are also studying the same stem cells in a mouse model of brain injury. Their aim is to provide an alternative to the scientific community's current attempts to coax blank-slate embryonic stem cells in the Petri dish to grow into neurons for treatment of conditions like Alzheimer's disease.

The Jan lab's work suggests a more direct route: If scientists understood the mechanisms that prompt the body's existing stem cells to regenerate specific tissue, they might be able to design drugs that enhance that process. "We may be able to coach these cells to do a better job of repairing," says Kuo.

Photo: Gabriela Hasbun

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