Researchers thought they had dealt their newborn mice a death blow by deleting the Numb and Numb-like genes in the neural progenitor cells of the subventricular zone (SVZ). Within 2 weeks of the conditional deletion, they saw massive enlargement of the ventricles and loss of cells lining the space and disappearance of the associated neuroprogenitor cells. Growth retardation was starting to set in.
But surprisingly, the mice did not die. In fact, by the time they were 6 months old, their brains had largely repaired the early damage. That surprising finding, reported in this week’s Cell from Yuh-Nung Jan and colleagues of the Howard Hughes Medical Institute at the University of California at San Francisco, revealed an unexpected capacity in the brain for self-repair and remodeling in the face of what looked like catastrophic damage to the stem cell niche.
While the results are not directly applicable to AD—the type of damage the disease causes is vastly different from Numb knockouts—it is a hopeful sign for the future prospects of harnessing the natural regenerative capacity of the brain to remedy some aspects of neurodegenerative disease.
The brain-repair story started as a search for genes that function to maintain and regulate the neural progenitor pool that persists in the SVZ throughout postnatal and adult life. First author Chay Kuo and colleagues developed a scheme to target these cells by expressing a tamoxifen-inducible Cre recombinase transgene under control of the progenitor-specific nestin promoter. They used the targeted Cre to create a conditional knockout in postnatal mice of a known regulator of embryonic neurogenesis, the Numb gene. By doing this in a background of a knockout of the Numb homolog, Numb-like, they could create mice double null for the two related genes.
The mice expressing a floxed Numb allele and null for Numb-like gene appeared completely normal, with no defects in postnatal brain development. But when the investigators gave the newborn mice one dose of tamoxifen, the results were dramatic. By 1 week later, the animals showed severe lateral ventricle enlargement. By 2 weeks, the cell layers that lined the ventricle walls were falling apart, and SVZ neuroblasts had mostly disappeared. The picture of destruction was consistent with the observed normal expression pattern of Numb protein in both the ependymal cells and neural progenitors that make up the SVZ stem cell complement, and showed an important role for the protein in both niche structure and progenitor cell survival.
But wait a minute. As the animals aged, rather than worsen and die, they survived into adulthood. When the investigators took a look at 6-week-old mice, they found a surprising result. Ventricle size was much smaller, and the ventricular walls had been repaired. The new wall tissue was different from the original, containing astrocytes as well as ependymal cells. But the repaired tissue was able to support neural progenitors, which the researchers found growing adjacent to the new wall. The cells responsible for the repair job were none other than Numb-positive, SVZ progenitors that had escaped the initial tamoxifen-induced deletion. Consistent with this result, there was no evidence of repair in mice repeatedly treated with tamoxifen.
"This is an excellent piece of work in basic stem cell biology," says neurologist S. Thomas Carmichael of the University of California at Los Angeles, who studies mechanisms of neuronal repair after stroke. "It indicates a great degree of plasticity in the stem cell niche in adult brain. It tells us this region can respond to damage through a change in its overall structure and still continue to produce immature neurons and neural progenitors. This data identifies a remodeling capacity in the stem cell germinal matrix of the adult brain."
While there are few diseases that directly damage the brain in the way Numb/Numb-like deletion did, many diseases, including AD, Parkinson disease, and stroke, signal to or influence the stem cells in the SVZ. "If the niche can change and repair itself so well in response to direct damage, diseases that stimulate it may be able to engender similar plasticity," Carmichael says.
A second paper, this one dealing with another kind of stem cell, shows that regulation of nuclear import of transcription factors affects the neuronal differentiation of mouse embryonic stem cells. The work, from Yoshihiro Yoneda and colleagues at Osaka University in Japan, appeared in Nature Cell Biology online this week.
Differentiation of stem cells often relies on changing patterns of master regulators of gene expression. But those factors themselves are subject to multiple tiers of regulation. One level may be the importin-α proteins, which bind to nuclear localization signals in cytosolic proteins including transcription factors, and so may gate the cytoplasmic-nuclear shuttling of these regulators of gene expression. First author Noriko Yasuhara and coworkers found that a switch in importin-α subtype expression occurs during induced neuronal differentiation of mouse ES cells in culture, from mainly importin-α1 to importin-α5. The switch is coordinated with the expression of transcription factors that promote differentiation, and forcing the switch by downregulating α1 or upregulating α5 is sufficient to change transcription factor expression and induce neuronal differentiation of the cells.
“We propose that nuclear transport factors should be considered as key coordinators in cell fate determination,” the authors write. Their next challenge will be to figure out what regulates the regulators.—Pat McCaffrey
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- Kuo CT, Mirzadeh Z, Soriano-Navarro M, Rasin M, Wang D, Shen J, Sestan N, Garcia-Verdugo J, Alvarez-Buylla A, Jan LY, Jan YN. Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. Cell. 2006 Dec 15;127(6):1253-64. PubMed.
- Yasuhara N, Shibazaki N, Tanaka S, Nagai M, Kamikawa Y, Oe S, Asally M, Kamachi Y, Kondoh H, Yoneda Y. Triggering neural differentiation of ES cells by subtype switching of importin-alpha. Nat Cell Biol. 2007 Jan;9(1):72-9. PubMed.