The role of p63 in normal epidermal differentiation and ectodermal dysplasias

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DESCRIPTION (provided by applicant): Project Summary: Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and clefting (AEC). I recently discovered that skin erosions that resemble those found in AEC patients develop in mice with reduced Delta-Np63 expression. The proposed studies will dissect the regulatory pathways by which Delta-Np63 controls normal epidermal homeostasis and will provide insight into the disease mechanism underlying AEC. Using gene expression profiling, I have identified three putative Delta-Np63 target genes, Frasl, Frem2, and Calml4, whose misexpression may contribute to the AEC phenotype. During the mentored phase of the award I will determine if Delta-Np63alpha directly regulates expression of the basement membrane components Frasl and Frem2. In addition, I will determine if Delta-Np63alpha regulates keratinocyte differentiation by directly inducing expression of the predicted calcium-binding protein Calml4. These studies will be performed in the laboratory of Dr. Dennis Roop at Baylor College of Medicine, which has a long history of outstanding research and mentorship of young scientists. As an independent investigator, I will generate inducible mouse models in which expression of Frasl, Frem2, or Calml4 can be downregulated in the epidermis. These mouse models will allow me to determine the role of Frasl and Frem2 in regulating basement membrane integrity in postnatal epidermis. Furthermore, I will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. My analysis of CalirM function in keratinocyte terminal differentiation will be completed by performing proteomics and microarray analysis. Ultimately, the proposed studies will contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, and may identify targets for novel therapeutic approaches aimed at treating this disease. Relevance: Skin erosions in patients with a skin fragility disease, AEC syndrome, are caused by mutations in a gene called p63. We have recently developed a mouse model for this disease, which will allow us to determine how defects in p63 cause skin erosions. These studies may lead to the development of novel therapeutic strategies for this disease and other diseases characterized by fragile skin.