Generating A Mouse Model For AEC Syndrome

December 2007
By Maranke I. Koster, PhD

Department of Dermatology and Regenerative Medicine and Stem Cell Biology Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO.

Recently, scientists found that changes in a specific gene, called p63, cause skin fragility in AEC patients. They found that the p63 gene plays an important role in the skin, because it acts as an "on and off switch" for other genes. The p63 gene produces six different proteins in varying amounts. In AEC patients, two of these six proteins are changed, and do not work as they should. The two mutated proteins are called TAp63Δ and ΔNp63Δ. In our previous studies, we found that TAp63Δ is active during very early stages of epidermal development, long before birth, whereas ΔNp63Δ is active during later stages of epidermal development shortly before birth, and also after birth. Since skin erosions in AEC patients are present after birth, we believe that mutant ΔNp63Δ is responsible for skin fragility in AEC patients.

To study how mutant ΔNp63Δ causes skin fragility, we needed to develop an animal model that mimicked AEC. The skin of mice is very similar to the skin of humans, so we started by working to create mice with alterations in p63. Because we found that mutant ΔNp63Δ cannot anymore turn on the genes that normal ΔNp63Δ turns on, we reasoned that we could mimic AEC in mice by lowering the amount of ΔNp63Δ in mouse skin. To do this, we first developed a molecule that degrades ΔNp63Δ.

Then, we generated a mouse that makes this molecule in the skin. Further, we designed the mouse in such a way that this molecule is only produced when the skin is treated with a chemical substance, called an inducer. After applying the inducer, the mouse’s skin has much less ΔNp63Δ than it should – and works very much like the skin of AEC patients. Further, since the ΔNp63Δ-degrading molecule is only produced in the area where the inducer is applied, we can reduce the amount of ΔNp63Δ in only a small patch of skin. For example, we can reduce ΔNp63Δ in only the footpads or in the back skin of mice by only putting the inducer on those areas. In all cases, the mice developed severe skin erosions only in the areas where we reduced ΔNp63Δ. These erosions looked very similar to those of AEC patients. However, just because they look the same does not mean that they are, in fact, similar. The only way to test this is to put samples of the skin of AEC patients and the skin of our mice under the microscope, and see if they are the same at the molecular level. In order to do this, we obtained skin biopsies (samples) from three patients with AEC and compared these samples with skin biopsies from our mouse model. We found that they were indeed similar at the molecular level.

Now that we have made a working mouse model for AEC, we are using these mice to further investigate the cause of skin erosions in AEC patients. For example, we are now in the process of singling out the genes that ΔNp63Δ normally turns on, but that are not turned on in AEC patients. Identifying these genes will help us understand more about how AEC works genetically. Once we understand AEC more completely, we can use our mouse model to develop and test future possibilities for treating skin erosions in AEC patients.

Acknowledgements

I would like to thank Stephanie Kadel for her help in editing this article. Research described in this article was performed in collaboration with Dr. Dennis R. Roop and was supported by grants from the National Foundation for Ectodermal Dysplasias and the National Institutes of Health.

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