Molecular mechanisms regulating DeltaNp63 expression and function during development and differentiation of mouse skin keratinocytes
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The skin is a multilayered stratified epithelium providing a protective barrier against dehydration and pathogenic insult. The transcription factor p63 plays an important role in the development of stratified epithelium of the skin and its appendages as evident by studies in knockout and transgenic mice. Indeed, mice with targeted deletion of the p63 gene exhibit striking defects in skin development including impaired epidermal stratification and differentiation, and lack of skin derivatives such as hair follicles and glandular structures. However, understanding the molecular mechanisms that underlie this phenotype has been complicated by both the early postnatal lethality of p63 null mice and the existence of multiple p63 isoforms. The p63 gene gives rise to multiple functionally distinct protein isoforms, including TAp63, which encodes for an amino terminal transactivation domain (TA); and ΔNp63, which lacks the N-terminal transactivation domain (ΔN), and is synthesized from an internal promoter. In addition, both TA and ΔN transcripts are differentially spliced at the 3' end generating proteins with unique C-termini, which are designated as α, β, and γ isoforms. The fact that all isoforms of p63 are absent in the knockout mouse has thus precluded the studies on the biological role of individual p63 proteins, in particular the ΔNp63 isoforms, which are predominantly expressed in skin epidermal keratinocytes. Despite these studies, many questions regarding the function of p63, in particular the ΔNp63 isoform, remain unanswered. It is not clear how ΔNp63 expression is regulated in skin keratinocytes. In addition, the role of ΔNp63 in the early commitment stages of epidermal morphogenesis has not been investigated. Finally, the relative contributions of the various ΔNp63 isoforms in the development of epithelia and epithelial appendages, will also be examined.