Epidermal cell junctions and their regulation by p63 in health and disease.

Abstract

As the outermost tissue of the body, the epidermis is the first physical barrier for any pressure, stress or trauma. Several specialized cell-matrix and cell-cell adhesion structures, together with an intracellular network of dedicated intermediate filaments, are required to confer critical resilience to mechanical stress. The transcription factor p63 is a master regulator of gene expression in the epidermis and in other stratified epithelia. It has been extensively demonstrated that p63 positively controls a large number of tissue-specific genes, including those encoding a large fraction of tissue-restricted cell adhesion molecules. Consistent with p63 functions in cell adhesion and in epidermal differentiation, heterozygous mutations clustered mainly in the p63 C-terminus are causative of AEC syndrome, an autosomal dominant disorder characterized by cleft palate, ankyloblepharon and ectodermal dysplasia associated with severe skin erosions, bleeding and infections. The molecular basis of skin erosions in AEC patients is not fully understood, although defects in desmosomes and in other cell junctions are likely to be involved. Here, we provide an extensive review of the different epidermal cell junctions that cooperate to withstand mechanical stress and on the mechanisms by which p63 regulates gene expression of their components in healthy skin and in AEC syndrome. Collectively, advancement in understanding the molecular mechanisms by which epidermal cell junctions precisely exert their functions and how p63 orchestrates their coordinated expression, will ultimately lead to insight into developing future strategies for the treatment of AEC syndrome and more in generally for diseases that share an overlapping phenotype.