The largest organ of our bodies, the skin is what separates us from the outside world. It holds body fluids in, preventing dehydration, and keeps harmful microbes out - without it we would succumb to infection. But exactly how this important organ forms to perform such diverse tasks has been largely a mystery. New research supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides some clues.

Working with mouse embryos, Elaine Fuchs, Ph.D., and her colleagues at Rockefeller University found that the epidermis (the outside layer of skin cells that covers the body surface) starts as a single layer of dividing cells attached to a dense meshwork of proteins called a basement membrane. This membrane provides growth-signaling molecules to the dividing cells and separates the epidermis from underlying tissue. As development proceeds, the epidermis begins to stratify to ultimately form a multilayered protective barrier through an unusual process involving asymmetric cell division: a mechanism by which one mother cell divides into two distinctly different daughter cells.

When these underlying skin cells divide, the researchers found, they can divide either laterally, to produce two similar cells; or perpendicularly, in which one daughter cell remains attached to the basement membrane and the other moves outward. During the course of division, the factors that promote cell growth are partitioned off in the cell that stays at the basement membrane. Other factors, which may be involved in the production of the barrier to invading microorganisms, are confined to the outward-moving cells, Fuchs says. These outward-moving cells eventually make it to the skin's surface where they provide a protective barrier until they are eventually sloughed off (or scraped off or burnt off) and replaced by new cells. All the while, cells at the basement membrane continue to divide asymmetrically to form these two different daughter cells.

"Once this process is set up, it is maintained," says Fuchs. "It persists in the adult epidermis."

With a basic understanding of the process of how cells divide and differentiate, the scientists have begun to use genetic studies in mice to try to identify which genes are necessary in the process. "We want to know what sets this up and how cells acquire the ability to divide perpendicularly," says Fuchs.

By understanding the normal mechanisms that control how stratified squamous epithelial tissues such as the epidermis are able to assemble their cells into their tissues and repair them in response to injury, Fuchs hopes to also gain a better understanding of how different disorders of the skin - from skin cancer to psoriasis - arise when various aspects of this normal mechanism become faulty.

Fuchs says insights from these studies may also be applicable to asymmetrical division in human stem cells: precursor cells that have the ability to grow into one or more of the body's more than 200 cell types. "The future will have to be unfolded before we can evaluate the extent to which our findings will be broadly relevant," she says.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 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

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Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 2005;(437):275-280.

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