Principal investigator Yuh-Nung Jan and his team developed a mutant line of mice that, upon receiving an injection just after birth, did not develop the genes Numb and Numblike in their brains' subventricular zones (SVZ), an area along the lateral wall of the lateral ventricles (two cavities) that are part of the brain's main communication hub. Jan previously determined that Numb, in drosophila fruit flies, played a role in the development of stem cells into neurons. Jan was not entirely sure, however, what role Numb and functionally related Numblike performed in the mammalian brain. By knocking out these genes, they were able to study their function.
When Jan autopsied some of his mutant mice one to two weeks after their birth, the mice had enlarged ventricles. "As it turned out," Jan says, "these proteins are very important for the integrity of the cellular junctions formed between the ependymal cells," which are cells that make up the ventricles' external lining. Not only were there essentially holes in the brains of these mice after two weeks, but the animals also showed noticeable disruptions in their growth cycles. In addition, according to Jan, "SVZ stem cells produce neuroblasts, [dividing cells that develop into nerve cells or neurons], that migrate to the mouse olfactory bulbs, and, when the SVZ was injured, these mice had smaller olfactory bulbs." Jan's group expected these mice to begin dying off at any moment.
But, they persisted.
By six weeks of age, the mice missing Numb and Numblike, had bigger olfactory bulbs and their growth had normalized significantly. When researchers examined the SVZs of these mice, they discovered that the ependymal cells of the ventricles had been jury-rigged together. After examining the replacement cells, the researchers found that they had developed the Numb protein. Apparently, "some of these SVZ stem cells escaped Numb deletion because of an imperfection in our genetic manipulation," Jan says. And "these escaper stem cells mediated the subsequent repair."
Jan's team believes the mechanism behind the rebuilding of these cells in their mouse models may one day be applied to treat neurological damage due to stroke or trauma in the human brain; after all, the cellular components and proteins are all present in humans. The next step is to determine how these stem cells sense damage and then begin to work on the injured tissue. "If we can figure out how this happens, and determine that it occurs in human neural stem cells," says Chay T. Kuo, a researcher in Jan's lab, "we may be able to increase the effect and harness it for therapeutic use."