The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human heredity syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die wihin few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (-80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endegenous Claudin-1 gene and a reporter vector containing a -1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the 1537T p63 mutation. Notably, AEC patients displays skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias. © 2008 Lopardo et al.

Lopardo, T., Lo Iacono, N., Marinari, B., Giustizieri, M.l., Cyr, D.g., Merlo, G., et al. (2008). Claudin-1 is a p63 target gene with a crucial role in epithelial development. PLOS ONE, 3(7), e2715 [10.1371/journal.pone.0002715].

Claudin-1 is a p63 target gene with a crucial role in epithelial development

MARINARI, BARBARA;COSTANZO, ANTONIO;
2008-01-01

Abstract

The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human heredity syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die wihin few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (-80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endegenous Claudin-1 gene and a reporter vector containing a -1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the 1537T p63 mutation. Notably, AEC patients displays skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias. © 2008 Lopardo et al.
2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/35 - MALATTIE CUTANEE E VENEREE
English
Con Impact Factor ISI
claudin 1; protein p63; isoprotein; membrane protein; phosphoprotein; transactivator protein; Trp63 protein, mouse; AEC syndrome; animal cell; animal tissue; article; controlled study; development; disease severity; down regulation; ectodermal dysplasia; embryo; epidermis; gene activation; gene expression regulation; gene mutation; gene silencing; gene targeting; genetic linkage; human; human tissue; in vivo study; keratinocyte; mouse; newborn; nonhuman; pathogenesis; phenotype; promoter region; protein binding; skin biopsy; skin epithelium; skin fragility; transcription regulation; animal; biological model; cytology; ectoderm; epithelium; metabolism; mutation; physiology; prenatal development; reporter gene; skin; Mus; Animals; Down-Regulation; Ectoderm; Epidermis; Epithelium; Gene Expression Regulation, Developmental; Genes, Reporter; Keratinocytes; Membrane Proteins; Mice; Models, Biological; Mutation; Phosphoproteins; Protein Isoforms; Skin; Trans-Activators
Lopardo, T., Lo Iacono, N., Marinari, B., Giustizieri, M.l., Cyr, D.g., Merlo, G., et al. (2008). Claudin-1 is a p63 target gene with a crucial role in epithelial development. PLOS ONE, 3(7), e2715 [10.1371/journal.pone.0002715].
Lopardo, T; Lo Iacono, N; Marinari, B; Giustizieri, Ml; Cyr, Dg; Merlo, G; Crosti, F; Costanzo, A; Guerrini, L
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34310
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