August 1, 2011

A team of scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, in collaboration with researchers at the National Cancer Institute, have discovered that deletion of a gene called Distal-less 3 (Dlx3) in mice is associated with the development of a type of skin inflammation that involves the cell-signaling molecule, interleukin-17 (IL-17). Their findings were published in the July 12 issue of the Proceedings of the National Academy of Sciences.

The team’s discovery is significant because it provides further insight into the complex network of cell-signaling molecules that appear to be involved in regulating the barrier function of the skin, as well as in the inflammatory processes that often accompany barrier disruption.

Skin protects the body from dehydration and external threats, such as microorganisms and harmful substances. Its function as a barrier is largely established by keratinocytes, cells in the outer layer of skin known as the epidermis. During skin development, these keratinocytes differentiate into more specialized cells that give healthy skin its ability to keep water in and germs out, while also regulating body temperature and protecting the nerve endings that facilitate the sense of touch.

The study’s lead author, Maria I. Morasso, Ph.D., chief of the NIAMS Developmental Skin Biology Section, said the research team knew from their previous work that expression of Dlx3 in the basal, or bottom, layer of skin resulted in a decreased rate of keratinocyte proliferation, and a premature end to the differentiation process that normally establishes a functional skin barrier. They further suspected that Dlx3 was important in skin because they had deleted the gene for Dlx3 expression in hair in a mouse model, and found that Dlx3 function was essential to hair follicle formation.

To test their hypothesis and to shed more light on the role of keratinocytes in the development of normal and abnormal skin, the team bred a strain of mice devoid of Dlx3 in the epidermis. The results:

  • keratinocytes in these mice proliferated at a much higher rate than normal;
  • the keratinocytes did not differentiate normally;
  • although the mice were able to establish barrier function, molecular indicators showed that the barrier was, on some level, compromised; and
  • the mice developed an inflammatory response characterized by the infiltration of the epidermis by white blood cells that produce IL-17.

Dr. Morasso says the team’s next goal is to investigate whether reduced expression or function of the Dlx3 gene are involved in aspects of inflammatory skin diseases, such as psoriasis or atopic dermatitis, which are also characterized by an increased proliferation rate of keratinocytes that differentiate abnormally.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), 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 website at


Hwang J, Kita R, Kwon HS, Choi EH, Lee SH, Udey MC, Morasso MI. Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation. Proc Natl Acad Sci USA. 2011 Jul 12; 108 (28):11566-11571.

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