Regeneration in Mice Through a Single Gene Deletion
You might recall the accidental discovery of unusually potent regeneration in MRL mice by Ellen Heber-Katz's team some years ago:
Our laboratory has determined that the MRL mouse strain is unique in its capacity for regenerative wound healing, as shown by the closure of ear punches with normal tissue architecture and cartilage replacement reminiscent of amphibian regeneration as opposed to scarring.
One line of research into regenerative medicine is based on understanding and then recreating in mammals the regenerative powers of lower animals like the salamander or zebrafish. The existence of MRL mice, a laboratory breed originally created for quite different reasons, provides hope that the required genetic or other alterations to mammalian biochemistry are not in fact insurmountably large or complex. Some researchers believe that mammals retain much of the salamander's regenerative capabilities encoded within their genome, and that it is currently only unused or inaccessible rather than completely lost.
But onwards: my eye was caught today by an update from Heber-Katz's laboratory, in which the regenerative capacity of MRL mice is matched up to a single genetic deletion:
A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander....
Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears.
Those of you so inclined might want to take a look at the paper; not open access, I'm afraid. But what does this mean for the future of mammals that regenerate like salamanders? It is hard to say at this stage, although one could speculate on the similarities between full regeneration in amphibians, cancerous growth in adults, and embryonic development. The gene p21 is fairly central to a range of mechanisms, and it is probably important that one of those mechanisms is cancer suppression; if adult tissue is undertaking controlled regrowth that bears many things in common with cancer, the normal cancer suppression mechanisms might interfere in that process. While mice lacking p21 are basically fairly normal (which is surprising, all things considered) there is every reason to expect wide-ranging and unpredictable side-effects to turn up on closer inspection:
A decline in adult stem cell function occurs during aging, likely contributing to the decline in organ homeostasis and regeneration with age. An emerging field in aging research is to analyze molecular pathways limiting adult stem cell function in response to macromolecular damage accumulation during aging. Current data suggest that the p21 cell cycle inhibitor has a dual role in stem cell aging: On one hand, p21 protects adult stem cells from acute genotoxic stress by preventing inappropriate cycling of acutely damaged stem cells. On the other hand, p21 activation impairs stem cell function and survival of aging telomere dysfunctional mice indicating that p21 checkpoint function is disadvantageous in the context of chronic and persistent damage, which accumulates during aging.
Still, learn by doing should be the mantra of modern biotechnology. The determination of a single gene of interest in this matter will lead researchers to investigate a narrow range of potential underlying mechanisms in order to explain why the MRL mice heal as they do. Those mechanisms can then be manipulated directly, one by one, to establish a better picture as to what exactly is going on here.
Khamilia Bedelbaeva, Andrew Snyder, Dmitri Gourevitch, Lise Clark, Xiang-Ming Zhang, John Leferovich, James M. Cheverud, Paul Lieberman, & Ellen Heber-Katz (2010). Lack of p21 expression links cell cycle control and appendage regeneration in mice PNAS : 10.1073/pnas.1000830107
If it interferes with the cancer suppression mechanism, it is probably important to investigate what the gene does (which proteins it codes for, what pathways it affects), so that it can lead to local treatment after an injury (eg injection of proteins at the site of the wound to prevent scarring and prompt regeneration instead), rather than the life-long, permanent modification that the MRL mice have.
@ [Posted by: Hervé Musseau at March 19, 2010 3:15 AM]
The healing properties are from the lack of the P21 expression which requires the lack not the addition of protein expression. To study the effects of what turning off P21 does would require even further research to understand how using some sort of chemical messenger interacts with turning off the expression.