p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation

Abstract

Heterozygous germline mutations in p63, a transcription factor of the p53 family, result in abnormal morphogenesis of the skin and its associated structures, including hair follicles and teeth. In mice lacking p63, all ectodermal organs fail to develop, and stratification of the epidermis is absent. We show that the ectodermal placodes that mark early tooth and hair follicle morphogenesis do not form in p63-deficient embryos, although the multilayered dental lamina that precedes tooth placode formation develops normally. The N-terminally truncated isoform of p63 (⌬Np63) was expressed at high levels in embryonic ectoderm at all stages of tooth and hair development, and it was already dominant over the transactivating TAp63 isoform prior to epidermal stratification. Bmp7, Fgfr2b, Jag1 and Notch1 transcripts were co-expressed with ⌬Np63 in wild-type embryos, but were not detectable in the ectoderm of p63 mutants. In addition, ␤-catenin and Edar transcripts were significantly reduced in skin ectoderm. We also demonstrate that BMP2, BMP7 and FGF10 are potent inducers of p63 in cultured tissue explants. Hence, we suggest that p63 regulates the morphogenesis of surface ectoderm and its derivatives via multiple signalling pathways.

p53/p63/p73 in the Epidermis in Health and Disease

“…The p63 isoforms play distinct roles in the control of epidermal development; the DNp63 isoforms are much more abundant in the epidermis compared to TAp63, which is strongly expressed in basal epidermal keratinocytes and is markedly down-regulated in the spinous epidermal layer (Laurikkala et al 2006;Romano et al 2009Romano et al , 2012LeBoeuf et al 2010;Shalom-Feuerstein et al 2011). TAp63 is also expressed in response to stresses such as wound healing (Su et al 2009b).…”

p63 in epithelial development

“…TAp63 isoform expression starts at E13, and only accounts for 1% of total p63 mRNA expressed at this embryonic stage. However, TAp63 isoforms have not been detected by in situ hybridization or immunoblot; thus TAp63 protein levels appear to be barey detectable [13,20]. Studies in ES-derived cells shows that BMP-4 treatment, leading to the ectodermal fate, induces Np63, while exogenous expression of the Np63 isoform in ES-derived ectodermal cells efficiently leads to their differentiation into keratinocytes [21].…”

p63 Overexpression Induces the Expression of Sonic Hedgehog

“…TAp63g has also been shown to activate the expression of Jagged 1 and Jagged 2, which are involved in Notch signaling, whereas Notch 1 activation has also been shown to suppress DNp63a expression, demonstrating a cross-talk between these pathways (7,8). Additional studies have shown that the biological effects of p63 in development and tumor suppression is exerted through the regulation of multiple signaling pathways (9)(10)(11)(12)(13)(14)(15)(16)(17). p73, another member of the p53 family, was also discovered based on structural similarities to p53 (18).…”