ΔNp63 knockdown mice: A mouse model for AEC syndrome

Abstract

Dominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since DNp63a is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant DNp63a proteins are primarily responsible for skin fragility in AEC patients. We found that mutant DNp63a proteins expressed in AEC patients function as dominant-negative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating DNp63a. Indeed, downregulating DNp63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by DNp63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions.

p63, a Story of Mice and Men

“…Through interference with structural stability of the epidermis, these defects likely contributed to the observed skin fragility. These data underscore the importance of DNp63 isoform expression in keratinocytes to maintain epidermal integrity by inducing the expression of several target genes (Vigano et al, 2006;Koster et al, 2007aKoster et al, , 2009). TAp63À/À mice carrying a deletion of the TA-specific exons 2 and 3 (Suh et al, 2006) and epidermal-specific TAp63À/À mice did not display any of these skin abnormalities (Su et al, 2009b), confirming that the TAp63 isoforms have no significant role (if at all) in epidermal differentiation or stratification.…”

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

“…This is caused, in part, by the lack of availability of skin samples for this rare disorder. We obtained skin biopsies from AEC patients, thus allowing us to interrogate abnormal expression of genes and proteins associated with skin integrity (Fete et al, 2009; Koster et al, 2009; Beaudry et al, 2009). Consistent with reports using smaller sample sets, our analysis of AEC patient skin revealed the presence of suprabasal proliferation, impaired terminal differentiation, and abnormal deposition of basement membrane components (Koster et al, 2009; Marinari et al, 2009; Clements et al, 2012; Browne et al, 2011; McGrath et al, 2001).…”

p53 Isoforms: An Intracellular Microprocessor?

“…88 Specific depletion of ΔNp63 isoforms in mouse epidermis causes severe epidermal defects, leading to the development of severe skin erosions indistinguishable from that of AEC patients. 89,90 As p53, p63, and p73 isoforms are expressed in a tissuedependent manner, it may explain why different human cell types respond differently to identical cellular damages. 91,92 The promoter selectivity and activation by p53, p63, and p73 are also regulated by cofactors such as ASPP1/ ASPP2/iASPP and posttranslational modifications such as phosphorylation and acetylation [93][94][95][96] (reviews 97,98 ).…”