p63 Induces Key Target Genes Required for Epidermal Morphogenesis

Epidermal morphogenesis is controlled by p63, a transcription factor that can be expressed as multiple isoforms. Of these, ΔNp63 isoforms are the predominantly expressed isoforms in late embryonic and postnatal epidermis. To determine the role of ΔNp63 proteins, we generated an epidermal‐specific inducible ΔNp63 knockdown mouse model. We found that downregulating ΔNp63 expression caused severe epidermal defects, including aberrant keratinocyte differentiation and impaired basement membrane formation, culminating in the development of severe skin erosions. Interestingly, these lesions were indistinguishable from lesions that develop in patients with AEC, a skin fragility disorder caused by mutations in ΔNp63α. We found that, during epidermal morphogenesis, ΔNp63α initially induces expression of Fras1, which is required for maintaining the integrity of the epidermal‐dermal interface at the basement membrane. Subsequently, ΔNp63α initiates epidermal terminal differentiation by inducing IKKα. Together, our data provide novel insights into the role of ΔNp63α in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations. This work was supported by grants from the NIH and the National Foundation for Ectodermal Dysplasias.