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p63 is a p53 homologue required for limb and epidermal morphogenesis

Abstract

The p53 tumour suppressor is a transcription factor that regulates the progression of the cell through its cycle and cell death (apoptosis) in response to environmental stimuli such as DNA damage and hypoxia1,2. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal3, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known4,5 and here we describe the function of p63 in vivo. Mice lacking p63 are born alive but have striking developmental defects. Their limbs are absent or truncated, defects that are caused by a failure of the apical ectodermal ridge to differentiate. The skin of p63-deficient mice does not progress past an early developmental stage: it lacks stratification and does not express differentiation markers. Structures dependent upon epidermal–mesenchymal interactions during embryonic development, such as hair follicles, teeth and mammary glands, are absent in p63-deficient mice. Thus, in contrast to p53, p63 is essential for several aspects of ectodermal differentiation during embryogenesis.

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Figure 1: Targeted disruption of the p63 locus.
Figure 2: The phenotype of p63-deficient newborn mice.
Figure 3: Analysis of p63-deficient limbs during embryogenesis.
Figure 4: Analysis of expression in wild-type and p63-deficient limbs.
Figure 5: p63 is required for development of the epidermis.
Figure 6: Expression of differentiation markers in p63-deficient epidermis.

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Acknowledgements

We thank S. Rivera for assistance with gene targeting, Y.-C. Cheah for blastocyst injection and for help with mapping the p63 locus, H. Zhang for sequencing, Y. Qi and J. Wesley for assistance in genotyping and maintaining the mouse colony, S. Vaishnav for histology and in situ hybridization, R. Johnson for constructs, for advice, and for critically reading the manuscript, and members of A.B.'s laboratory, particularly G. Luo and M. Mills for discussions, P. Biggs for reviewing the text, and S. Perez for help in preparing it. A.B. is an Investigator and A.M. is a Research Associated with the Howard Hughes Medical Institute. A.B. and D.R.R. acknowledge support from the National Cancer Institute.

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Correspondence to Allan Bradley.

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Mills, A., Zheng, B., Wang, XJ. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999). https://doi.org/10.1038/19531

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