p63 induces key target genes required for epidermal morphogenesis

Abstract

Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (⌬N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. ⌬Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that ⌬Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two ⌬Np63␣ target genes that mediate these processes. We propose that ⌬Np63␣ initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I B kinase-␣ by ⌬Np63␣ initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of ⌬Np63␣ in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

“…34 NF-kB activates the FLIP promoter, [38][39] and its regulator IkB kinase a is induced by DNp63a. 40 The FLIP promoter is therefore at the centre of converging and interconnected survival pathways -p63 and NF-kB -as well as proapoptotic signals (c-jun). Hence, caspase-8 and FLIP are linked by a common fate, regulated at the transcriptional, post-transcriptional and post-translational levels.…”

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

“…In contrast, OSK reprogramming upregulates epithelial genes and therefore requires p63 as a known epithelial master regulator. 39,[44][45][46][47][48] Of note, we found that p63/DNp63 À / À MEFs are also strongly impaired in OSKM reprogramming, a factor combination also known to induce MET 11,14 (Supplementary Figure 8). It remains to be identified which specific p63 transcriptional targets are involved in MET and reprogramming in general, and how they differ from those that mediate p63 function in epithelial development.…”

“…44 Specifically, DNp63 is highly expressed in the basal layer of epidermis, largely drives keratinocyte differentiation in vivo and is proposed to be responsible for maintenance of epidermal progenitor/stem cells. [45][46][47][48] Similarly, TAp63 is expressed in hair follicle bulge cells and dermal papillae cells (niches for epidermal and dermal stem cells, respectively) and is implicated in the maintenance of adult dermal and epidermal precursors. 49 Thus, both TAp63 and DNp63 could in principle be involved in reprogramming, given the stem cell-like nature of iPSCs.…”

p63 in epithelial development

“…Simultaneous knockdown of p53 in the context of p63 loss is able to rescue cell proliferation, however the differentiation defect is still present [29]. These data [27,29] are therefore somewhat in contrast with the results from Roop's group [24,31], who showed that, in vivo siRNA for TAp63 produced a dramatic phenotype, with failure to organize pluristratified epithelia but no significant effect was observed on the basal layer. However, in our model [27] we investigated the role in early development using a genetically pure model, with the total absence of one isoform, the elegant in vivo study by Roop using siRNA addressed a slightly different question, representing a model of isoform unbalance.…”