Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology

St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
British Journal of Dermatology (Impact Factor: 4.28). 02/2012; 167(1):134-44. DOI: 10.1111/j.1365-2133.2012.10888.x
Source: PubMed


AEC (ankyloblepharon-ectodermal defects-clefting) syndrome is an autosomal dominant ectodermal dysplasia disorder caused by mutations in the transcription factor p63. Clinically, the skin is dry and often fragile; other features can include partial eyelid fusion (ankyloblepharon), hypodontia, orofacial clefting, sparse hair or alopecia, and nail dystrophy.
To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin.
We performed microarray analysis on samples of intact and eroded AEC syndrome skin compared with control skin. Changes were verified by quantitative real-time reverse transcription-polymerase chain reaction and, for basal keratinocyte-associated genes, by immunohistochemistry and analysis of microdissected skin.
We identified significant upregulation of six genes and downregulation of 69 genes in AEC syndrome skin, with the main changes in genes implicated in epidermal adhesion, skin barrier formation and hair follicle biology. There was reduced expression of genes encoding the basement membrane proteins FRAS1 and collagen VII, as well as the skin barrier-associated small proline-rich proteins 1A and 4, late cornified envelope protein 5A, hornerin, and lipid transporters including ALOX15B. Reduced expression of the hair-associated keratins 25, 27, 31, 33B, 34, 35, 81 and 85 was also noted. We also confirmed similar alterations in gene expression for 26 of the 75 genes in eroded AEC scalp skin.
This study identifies specific changes in skin structural biology and signalling pathways that result from mutant p63 and provides new molecular insight into the AEC syndrome phenotype.

Download full-text


Available from: Celine Pourreyron
  • Source
    • "To gain insight into further pathways impacted, intact and eroded AEC syndrome skin and normal skin were compared by microarray analysis. The findings revealed changes in expression of genes associated with epidermal adhesion, skin barrier formation, and hair follicle biology, all consistent with the clinical presentation [48]. Thus, SAM domain mutations highlight the importance of p63 and in particular ΔNp63α to normal epidermal morphogenesis/homeostasis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers. In vitro keratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NF κ B/c-Rel as a downstream effector of p63 has identified a role for NF κ B/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression.
    Full-text · Article · Apr 2013
  • Source
    • "During embryonic development, progenitor cell expansion is affected due to impairment of fibroblast growth factor signalling leading to a defective epidermal stem cell compartment (45). Despite epidermal hypoplasia, epidermal differentiation occurs normally in p63+/L514F newborn mice, and the impermeable epidermal barrier is established at the appropriate developmental time-point consistent with little or no alteration of terminal differentiation observed in the skin of AEC patients (18,46). Here, we demonstrate that in AEC syndrome skin fragility is associated with acantholysis and reduced desmosomes between the basal and suprabasal layers of the epidermis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 EGFR 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.
    Full-text · Article · Oct 2012 · Human Molecular Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: More than 100 human genetic skin diseases, impacting over 20% of the population, are characterized by disrupted epidermal differentiation. A significant proportion of the 90 genes identified in these disorders to date are concentrated within several functional pathways, suggesting the emergence of organizing themes in epidermal differentiation. Among these are the Notch, transforming growth factor β (TGFβ), IκB kinase (IKK), Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), p63, and Wnt signaling pathways, as well as core biological processes mediating calcium homeostasis, tissue integrity, cornification, and lipid biogenesis. Here, we review recent results supporting the central role of these pathways in epidermal differentiation, highlighting the integration of genetic information with functional studies to illuminate the biological actions of these pathways in humans as well as to guide development of future therapeutics to correct their dysfunction.
    No preview · Article · Nov 2012 · Trends in Genetics
Show more