Deleting a Gene May Allow Mammalian Limb Regeneration

A recent study found that by preventing expression of a single gene it was possible to restore in a mouse model the potential for regeneration of a lost limb.

Mammals generally lack the capability to regenerate multiple tissue types, organs, and appendages after injury although some types of animals including some sponge, hydra, planarian, and salamander species do retain this ability.

The one mammal that has been shown in the laboratory to be capable of regenerating complex tissues it the MRL mouse, which is able to generate tissue to close holes punctured in their ears. Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation. At the molecular level, cells from MRL mice lack the p21 gene. Absence of this gene, which is under the direct control of the p53 tumor suppressor, is a characteristic trait of mouse embryonic stem cells.

To investigate further the role of p21, researchers at the Wistar Institute (Philadelphia, PA, USA) genetically engineered a different, unrelated mouse strain to lack p21 expression. They reported in the March 15, 2010, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that these animals closed ear holes similar to MRL mice, providing a firm link between this gene and tissue regeneration. Wild type mice with active p21 failed to close ear holes.

"In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous,” said senior author Dr. Ellen Heber-Katz, professor of cellular and molecular oncogenesis at the Wistar Institute. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported. The combined effects of an increase in highly regenerative cells and apoptosis may allow the cells of these organisms to divide rapidly without going out of control and becoming cancerous. In fact, it is similar to what is seen in mammalian embryos, where p21 also happens to be inactive after DNA damage. The down regulation of p21 promotes the induced pluripotent state in mammalian cells, highlighting a correlation between stem cells, tissue regeneration, and the cell cycle.”

"Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said Dr. Heber-Katz. "While we are just beginning to understand the repercussions of these findings, perhaps, one day we will be able to accelerate healing in humans by temporarily inactivating the p21 gene.”

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Wistar Institute