Abstract
Simple SummaryThe protein p63 belongs to the family of the p53 tumor suppressor. Mouse models have, however, shown that it is not a classical tumor suppressor but instead involved in developmental processes. Mutations in the p63 gene cause several developmental defects in human patients characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia due to p63’s role as a master regulator of epidermal development. In addition, p63 plays a key role as a quality control factor in oocytes and p63 mutations can result either in compromised genetic quality control or premature cell death of all oocytes.The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.
Highlights
Failure to maintain cellular homeostasis is a common driver of diseases like cancer and neurodegeneration, and plays a role in ageing, immunological, and metabolic disorders
Stabilization of p53 triggers its binding to promotor regions of certain genes, which results in the transcription of genes involved in DNA repair, senescence, cell cycle arrest, and apoptosis [5,6,7,8]
Transient epithelial structures during development are affected in the p63−/− mouse, such as the apical ectodermal ridge (AER) on the limb buds, a region of specialized, multilayered epithelium, which is essential for the development of distal limbs, digit patterning, and morphogenesis [66,67], and defects in AER lead to limb abnormalities
Summary
Failure to maintain cellular homeostasis is a common driver of diseases like cancer and neurodegeneration, and plays a role in ageing, immunological, and metabolic disorders. The developmental function of p63 in epithelial tissues is based on a different isoform, ∆Np63α The importance of this isoform for epidermal development was further shown by a knockout mouse model with specific inactivation of the ∆Np63 isoforms, which shows the same epithelial defects as the p63−/− mouse [52] as well as by the rescue of the p63−/− phenotype by expressing ∆Np63α under the K5 promoter [53]. Transient epithelial structures during development are affected in the p63−/− mouse, such as the apical ectodermal ridge (AER) on the limb buds, a region of specialized, multilayered epithelium, which is essential for the development of distal limbs, digit patterning, and morphogenesis [66,67], and defects in AER lead to limb abnormalities In addition to these squamous stratified epithelial tissues, p63 is expressed in pseudo-stratified epithelia such as the epithelium of the trachea where p63 is found in the basal cell layer [21].
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