Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.
Bottom Line: The AEC mutation exerts a selective dominant-negative function on wild-type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment.These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3, direct p63 target genes.Restoring Fgfr2b expression in p63(+/L514F) epithelial cells by treatment with FGF7 reactivates downstream mitogen-activated protein kinase signalling and cell proliferation.
Affiliation: Fondazione IRCCS SDN, Napoli, Italy.Show MeSH
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Mentions: To provide further support for Fgfr2b or other FGF signalling components being affected in p63+/L514F embryos, we first measured the expression levels of FGF receptors in mutant and wild-type tissues. Fgfr2b mRNA was significantly reduced in p63+/L514F palatal shelves, skin and primary keratinocytes as compared to controls (Fig 4A and B), whereas its expression was unaffected in p63+/− skin (Supporting Information Fig S6B). Among the other FGF receptors, expression of the epidermal-specific isoform Fgfr3b, which plays a role in promoting both epidermal cell proliferation and differentiation (Mandinova et al, 2009), was significantly reduced in p63+/L514F tissue and cells as compared to p63+/− and wild-type controls (Fig 4A). In contrast, Fgfr1 and Fgfr4 were expressed equally in mutant and wild-type embryonic tissues (Supporting Information Table S2).