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 characterize the developmental alterations that occur in AEC syndrome, we generated a knock-in mouse model carrying a leucine to phenylalanine substitution in position 514 (L514F) in the p63 protein (Fig 1A–D). L514 is a highly conserved amino acid in the first helix of the SAM domain, which is mutated to either phenylalanine or valine in AEC patients (McGrath et al, 2001; Payne et al, 2005; Supporting Information Fig S1A). A correctly targeted embryonic stem cell line allowed the mutation to be transmitted through germline to produce heterozygous p63+/L514F mice. p63 messenger RNA (mRNA) was expressed at similar levels in p63+/L514F mutant and in wild-type epidermis (Supporting Information Fig S1B), whereas p63 protein was more abundant in mutant than in wild-type epidermis (Supporting Information Fig S1C-D) consistent with the previously reported p63 accumulation in the skin of AEC patients (Browne et al, 2011; Moretti et al, 2010). No aberrant isoforms were detected either at the RNA or the protein levels (Supporting Information Fig S1C and S1E).