Master regulatory role of p63 in epidermal development and disease

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Abstract

The transcription factor p63 is a master regulator of epidermal development. Mutations in p63 give rise to human developmental diseases that often manifest epidermal defects. In this review, we summarize major p63 isoforms identified so far and p63 mutation-associated human diseases that show epidermal defects. We discuss key roles of p63 in epidermal keratinocyte proliferation and differentiation, emphasizing its master regulatory control of the gene expression pattern and epigenetic landscape that define epidermal fate. We subsequently review the essential function of p63 during epidermal commitment and transdifferentiation towards epithelial lineages, highlighting the notion that p63 is the guardian of the epithelial lineage. Finally, we discuss current therapeutic development strategies for p63 mutation-associated diseases. Our review proposes future directions for dissecting p63-controlled mechanisms in normal and diseased epidermal development and for developing therapeutic options.

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p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

A. Yang, R Schweitzer, D. Sun … (1999)

The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.

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p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.

A. Yang, M Kaghad, Y Wang … (1998)

We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.

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p63 is a p53 homologue required for limb and epidermal morphogenesis.

Alea A Mills, Binhai Zheng, Xiao-Jing Wang … (1999)

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 hypoxia. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known 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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Author and article information

Contributors

Eduardo Soares: 0031-24-3614255 , e.soares@science.ru.nl

Huiqing Zhou:

ORCID: http://orcid.org/0000-0002-2434-3986

0031-24-3616851 , jo.zhou@radboudumc.nl , j.zhou@science.ru.nl

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell. Mol. Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 4 November 2017

Publication date PMC-release: 4 November 2017

Publication date (Print): 2018

Volume: 75

Issue: 7

Pages: 1179-1190

Affiliations

[1 ]ISNI 0000000122931605, GRID grid.5590.9, Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, , Radboud University, ; 274, Postbus 9101, 6500HB Nijmegen, The Netherlands

[2 ]ISNI 0000 0000 9738 4872, GRID grid.452295.d, CAPES Foundation, Ministry of Education of Brazil, ; Brasília, Brazil

[3 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Human Genetics, , Radboud University Medical Center, ; 855, Postbus 9101, 6500HB Nijmegen, The Netherlands

Author information

Huiqing Zhou http://orcid.org/0000-0002-2434-3986

Article

Publisher ID: 2701

DOI: 10.1007/s00018-017-2701-z

PMC ID: 5843667

PubMed ID: 29103147

SO-VID: 19e65d27-a0da-4e2f-9bd3-0261fb3af899

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 30 May 2017

Date revision received : 16 October 2017

Date accepted : 26 October 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;

Award ID: NWO/ALW/MEERVOUD/836.12.010

Award Recipient : Huiqing Zhou

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ScienceOpen disciplines: Molecular biology

Keywords: epidermis,gene regulation,ectodermal dysplasia,epidermal cell identity,epigenetics

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ScienceOpen disciplines: Molecular biology

Keywords: epidermis, gene regulation, ectodermal dysplasia, epidermal cell identity, epigenetics

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Master regulatory role of p63 in epidermal development and disease

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Entomologia Generalis

Most cited references 89

p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.

p63 is a p53 homologue required for limb and epidermal morphogenesis.

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