Researchers supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases have discovered a molecule that keeps cells in the outer layers of skin from proliferating in mice. Their finding, to be published in the March 13 issue of Nature, could lead to a better understanding of skin cancer and open up new avenues of therapeutic research.

Healthy skin is maintained through the capacity of stem cells that reside in the deepest layer of skin, called the basal layer, to renew themselves. The cells that originate from these stem cells proliferate and migrate to the outer layers of skin, called the suprabasal layers. Here, they stop dividing, and begin to differentiate into specialized skin cells that form the barrier that protects your body from the world outside.

Because cancerous skin cells are characterized by out-of-control proliferation, cancer researchers are interested in any mechanism that the body has evolved to prevent suprabasal skin cells from continuing to divide. Such a mechanism could influence therapeutic research.

The molecule that the scientists identified, microribonucleic acid-203 (microRNA-203, or miR-203) is one of the most abundant of the more than 100 microRNAs expressed in skin. MicroRNAs are tiny pieces of RNA that bind to regions of messenger RNAs in order to regulate the production of proteins. Because microRNAs do not encode proteins themselves, their only role is to act as switches that stimulate or suppress a certain kind of protein production, says Rui Yi, Ph.D., a postdoctoral associate with Elaine Fuchs, Ph.D., in the Laboratory of Mammalian Cell Biology and Development at The Rockefeller University in New York City. Specifically, miR-203 suppresses the production of a protein called p63, which is known to drive cell proliferation.

Knowing of the regulatory role played by microRNAs, Fuchs and Yi, as well as colleagues at the Swiss Federal Institute of Technology in Zurich, suspected that one or more microRNAs might be involved in skin formation. By examining libraries of microRNAs from skin cells that were taken from mice at different stages of development — ranging from 13.5 days after conception to 4.5 days after birth — the scientists found their first clue that miR-203 might be one reason that normal suprabasal skin cells don't proliferate: in the cells taken 13.5 days after conception, when mouse skin stem cells have not yet differentiated, miR-203 expression was essentially nonexistent. But 2 days later, when the stem cells in mouse skin are known to begin the differentiation program, the levels of miR-203 were very high, suggesting an association between miR-203 and differentiation.

To test the association, Yi and his colleagues measured miR-203 levels in the different layers of mouse skin. Not surprisingly, the basal cell layer, with the stem cells, showed little if any miR-203. The suprabasal layers, however, which contain the cells that have already differentiated into mature skin cells, had high levels of miR-203.

Next, the scientists tried to determine miR-203's function by engineering mice to express the molecule in the stem cells of the basal layer, where it is not normally found. These mice died shortly after birth. Subsequent examination showed that the mice had significantly reduced numbers of skin stem cells, and, furthermore, that the stem cells had stopped proliferating, as if they had already differentiated. Therefore, the mice were unable to maintain the stem cell population in the basal layer of the skin.

In related research, Fuchs and Yi found that the skin cells of other vertebrates, including humans, showed miR-203 expression similar to mice. Yi says, "This is actually a clever way to protect your skin, so that the outer cells, which receive the most damage from the sun's rays and other environmental hazards, don't proliferate — they just protect the body until you shed them. On the other hand, the proliferating stem cells, in the basal layer, are protected by the suprabasal cells so they can replenish the skin."

A better understanding of miR-203 could lead to a better understanding of skin cancer. Yi says, "You need miR-203 expressed at high levels to repress proliferation of differentiated skin cells. If it becomes abnormally low, an area gets proliferation. That would be the obvious hallmark of cancer."

Yi is a recipient of an NIH Pathway to Independence Award. This award program was established in 2007 to help the most promising new investigators transition from a postdoctoral research position to a stable independent research position with research-funding support. Through this program, the NIH hopes to increase and maintain a strong cohort of new and talented NIH-supported independent investigators.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

###

Yi, R. et al. A skin microRNA promotes differentiation by repressing ‘stemness.’ Nature 2008; Published online: 2 Mar 2008: doi:10.1038/ng571.