Dissecting the molecular mechanisms underlying epidermal defects in AEC syndrome

AEC (Ankyloblepharon- Ectodermal defects- Cleft lip/palate) syndrome is an autosomal dominant disorder mainly characterized by closure of eyelids margins, ectodermal dysplasia, skin erosions, and cleft lip and/or palate. Skin erosions appear at birth or soon after, are often devastating and can last several years, resulting in recurrent infections. This disorder is caused by missense mutations in the transcription factor p63, a crucial regulator of skin development. We previously characterized an AEC mouse model that faithfully recapitulated the skin defects and cleft palate found in AEC patients. Using this model we found that AEC mice have a reduced epidermal cell growth, leading to skin hypoplasia and a reduced number of epidermal stem cells at birth. The usefulness of this mouse model was limited by its neonatal lethality due to cleft palate. Since our main objective is the analysis of the molecular basis of the epidermal fragility, we propose the characterization of other two mouse models that we recently generated: one in which the AEC mutation can be conditionally induced, thereby overcoming neonatal lethality, and the second one in which p63α, the isoform that is affected by AEC mutations, is conditionally deleted. Using these models we will characterize the defects in cell adhesion and in the stem cell compartment that are likely to be at the basis of the skin erosions. Characterization of these mouse models will also help us to identifying the biochemical mechanisms underlying the disease, which may lead to identification of currently available drugs or small compounds that could be tested in the AEC mouse model. Finally, we generated a small interfering RNA able to specifically targeting the mutation that will be used to explore the mechanism of action of the mutant p63, but at the same time will be tested for therapeutic purposes.