DeltaNp63 regulates the expression of critical genes involved in the development and differentiation of skin keratinocytes
Ortt, Kori Michelle
MetadataShow full item record
The largest organ of our body, the skin, provides a protective barrier against dehydration, mechanical traumas, chemicals, and other foreign substances. The skin is composed of the outermost epidermis that rests on a basement membrane separating it from the underlying extracellular matrix-rich dermis. A tightly controlled program of differentiation is required for the formation of the interfollicular epidermis that is essential for establishing the primary barrier of the skin. One transcription factor that is vital for this program is p63, which is predominantly expressed in the basal keratinocytes of the epidermis. The p63 gene is expressed from two different promoters and undergoes alternative splicing at the 3' carboxy terminus generating six different isoforms. The functional role of p63 became apparent by p63 knockout animals which fail to form a skin epidermis and epithelial appendages. To better understand the molecular mechanism by which p63 functions I have used a biochemical approach to identify the DNA consensus sequence found in the regulatory elements of p63 target genes, which is distinctly different from other family members. Target genes of p63 were identified by a chromatin immunoprecipitation approach in keratinocytes. Lastly, to begin to tease out the function of different isoforms of p63 in epidermal morphogenesis, I used a gain-of-function mouse model system to overexpress ΔNp63β in the suprabasal layers of the skin epidermis. Overexpression of ΔNp63β is associated with a block in terminal differentiation suggesting a role for this isoform in maintaining keratinocytes in an undifferentiated state. Finally, this work has begun to reveal the network of downstream signaling pathways and target genes regulated by p63 and has shed light on the molecular mechanism by which this transcription regulates epithelial proliferation and differentiation during skin epidermal development.