Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf

• Published in: The EMBO journal Vol. 28; no. 13; pp. 1904 - 1915
• Main Authors: Su, Xiaohua, Cho, Min Soon, Gi, Young-Jin, Ayanga, Bernard A, Sherr, Charles J, Flores, Elsa R
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 08.07.2009; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: adhesion; ADP-Ribosylation Factors - genetics; ADP-Ribosylation Factors - metabolism; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; differentiation; epidermal stem cells; Female; Gene expression; Gene Expression Regulation, Developmental; Genotype & phenotype; Inactivation; Ink4a-Arf; Keratinocytes - cytology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; p63-isoforms; Phenotype; Phosphoproteins - genetics; Phosphoproteins - metabolism; Pregnancy; Rodents; Skin; Skin - cytology; Skin - embryology; Skin - metabolism; Stem cells; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.151

Mice lacking p63 cannot form skin, exhibit craniofacial and skeletal defects, and die soon after birth. The p63 gene regulates a complex network of target genes, and disruption of p63 has been shown to affect the maintenance of epithelial stem cells, the differentiation of keratinocytes, and the preservation of the adhesive properties of stratified epithelium. Here, we show that inactivation of p63 in mice is accompanied by aberrantly increased expression of the Ink4a and Arf tumour suppressor genes. In turn, anomalies of the p63‐null mouse affecting the skin and skeleton are partially ameliorated in mice lacking either Ink4a or Arf. Rescue of epithelialization is accompanied by restoration of keratinocyte proliferative capacity both in vivo and in vitro and by expression of markers of squamous differentiation. Thus, in the absence of p63, abnormal upregulation of Ink4a and Arf is incompatible with skin development.