p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome

Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility ass...

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Main Authors:	Ferone, Giustina, Mollo, Maria Rosaria, Thomason, Helen A., Antonini, Dario, Zhou, Huiqing, Ambrosio, Raffaele, De Rosa, Laura, Salvatore, Domenico, Getsios, Spiro, van Bokhoven, Hans, Dixon, Jill, Missero, Caterina
Format:	Online
Language:	English
Published:	Oxford University Press 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542863/

id	pubmed-3542863
recordtype	oai_dc
spelling	pubmed-35428632013-01-11 p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome Ferone, Giustina Mollo, Maria Rosaria Thomason, Helen A. Antonini, Dario Zhou, Huiqing Ambrosio, Raffaele De Rosa, Laura Salvatore, Domenico Getsios, Spiro van Bokhoven, Hans Dixon, Jill Missero, Caterina Articles Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility associated with severe skin erosions after birth. Using a knock-in mouse model for AEC syndrome, we found that skin fragility was associated with microscopic blistering between the basal and suprabasal compartments of the epidermis and reduced desmosomal contacts. Expression of desmosomal cadherins and desmoplakin was strongly reduced in AEC mutant keratinocytes and in newborn epidermis. A similar impairment in desmosome gene expression was observed in human keratinocytes isolated from AEC patients, in p63-depleted keratinocytes and in p63 null embryonic skin, indicating that p63 mutations causative of AEC syndrome have a dominant-negative effect on the wild-type p63 protein. Among the desmosomal components, desmocollin 3, desmoplakin and desmoglein 1 were the most significantly reduced by mutant p63 both at the RNA and protein levels. Chromatin immunoprecipitation experiments and transactivation assays revealed that p63 controls these genes at the transcriptional level. Consistent with reduced desmosome function, AEC mutant and p63-deficient keratinocytes had an impaired ability to withstand mechanical stress, which was alleviated by epidermal growth factor receptor inhibitors known to stabilize desmosomes. Our study reveals that p63 is a crucial regulator of a subset of desmosomal genes and that this function is impaired in AEC syndrome. Reduced mechanical strength resulting from p63 mutations can be alleviated pharmacologically by increasing desmosome adhesion with possible therapeutic implications. Oxford University Press 2013-02-01 2012-10-29 /pmc/articles/PMC3542863/ /pubmed/23108156 http://dx.doi.org/10.1093/hmg/dds464 Text en © The Author 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ferone, Giustina Mollo, Maria Rosaria Thomason, Helen A. Antonini, Dario Zhou, Huiqing Ambrosio, Raffaele De Rosa, Laura Salvatore, Domenico Getsios, Spiro van Bokhoven, Hans Dixon, Jill Missero, Caterina
spellingShingle	Ferone, Giustina Mollo, Maria Rosaria Thomason, Helen A. Antonini, Dario Zhou, Huiqing Ambrosio, Raffaele De Rosa, Laura Salvatore, Domenico Getsios, Spiro van Bokhoven, Hans Dixon, Jill Missero, Caterina p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
author_facet	Ferone, Giustina Mollo, Maria Rosaria Thomason, Helen A. Antonini, Dario Zhou, Huiqing Ambrosio, Raffaele De Rosa, Laura Salvatore, Domenico Getsios, Spiro van Bokhoven, Hans Dixon, Jill Missero, Caterina
author_sort	Ferone, Giustina
title	p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
title_short	p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
title_full	p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
title_fullStr	p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
title_full_unstemmed	p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome
title_sort	p63 control of desmosome gene expression and adhesion is compromised in aec syndrome
description	Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility associated with severe skin erosions after birth. Using a knock-in mouse model for AEC syndrome, we found that skin fragility was associated with microscopic blistering between the basal and suprabasal compartments of the epidermis and reduced desmosomal contacts. Expression of desmosomal cadherins and desmoplakin was strongly reduced in AEC mutant keratinocytes and in newborn epidermis. A similar impairment in desmosome gene expression was observed in human keratinocytes isolated from AEC patients, in p63-depleted keratinocytes and in p63 null embryonic skin, indicating that p63 mutations causative of AEC syndrome have a dominant-negative effect on the wild-type p63 protein. Among the desmosomal components, desmocollin 3, desmoplakin and desmoglein 1 were the most significantly reduced by mutant p63 both at the RNA and protein levels. Chromatin immunoprecipitation experiments and transactivation assays revealed that p63 controls these genes at the transcriptional level. Consistent with reduced desmosome function, AEC mutant and p63-deficient keratinocytes had an impaired ability to withstand mechanical stress, which was alleviated by epidermal growth factor receptor inhibitors known to stabilize desmosomes. Our study reveals that p63 is a crucial regulator of a subset of desmosomal genes and that this function is impaired in AEC syndrome. Reduced mechanical strength resulting from p63 mutations can be alleviated pharmacologically by increasing desmosome adhesion with possible therapeutic implications.
publisher	Oxford University Press
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542863/
_version_	1611946327991648256

p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome

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