Cells' root: adult stem cells have a master gene.

A person's body constantly sheds dead skin cells, and new cells well up to take their places. Stem cells in the skin generate this continuous stream of biological units. Now, researchers have identified a master gene that enables these stem cells to retain their regenerative capacity.

The gene, called p63, is crucial for the maintenance of stem cell lines in epithelial tissues including skin, thymus, prostate, and breast, say Frank McKeon of the Harvard Medical School in Boston and his coworkers. An adult stem cell spawns a daughter cell that then develops into one of the various cell types within a particular organ. This process raises the possibility of treatments in which doctors would use stem cells to regenerate damaged tissues.

But each time a stem cell divides, only one daughter cell matures into a specific cell type. The other must retain its flexibility and remain in the reservoir of adult stem cells in an organ. The p63 gene orchestrates this action in epithelial tissue, the researchers say. Earlier work identified other master genes for stem cells for blood and for sperm.

The team found that mouse embryos lacking p63 began forming skin but soon stopped. In early stem cell divisions, both daughter cells matured into specialized skin cells, thereby depleting the supply of skin stem cells. Many of these mice were born almost skinless, the researchers report in the May 4 Cell.

"It's a very dramatic effect," says McKeon. "I think we've definitely shown now that p63 is the crux of stemness."

The gene acts as a master regulator, controlling the activity of about 2,000 other genes in the stem cells. Scientists don't yet know the pattern of gene activity that p63 triggers or how that activity makes a cell capable of spawning another stem cell.

The role of p63 in epithelial stem cells has been controversial. Other research groups had concluded that p63 is essential for the maturation of the daughter cells, not for the maintenance of the stem cell lineage. But those groups had looked at newborn p63-deficient mice delivered vaginally. McKeon says that the mice's passage through the birth canal had sloughed off the small amount of skin that had formed, leading the scientists to conclude that no skin cells had matured.

McKeon and his colleagues looked instead at the skin and thymus of mid- to full-term fetal mice surgically removed from their mothers. The scientists found some mature skin and thymus cells but a lack of epithelial stem cells.

"I think this paper will be cited in the field for having resolved the question" of p63's role, comments Elaine Fuchs of Rockefeller University, who studies epithelial stem cells.

McKeon says that information about the genetics of stem cells might suggest new therapies for several diseases.