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: Loss of p63 has been reported to affect the proliferative potential of stratified epithelial stem cells, including those of the skin (Senoo et al, 2007). To explore the possibility that mutant p63 may affect the pool of epidermal self-renewing cells, we first tested whether p63+/L514F cells have an altered clonogenic potential by plating freshly isolated newborn keratinocytes at clonogenic density and analyzing their ability to form clones over time. Initial plating efficiency was similar between mutant and wild-type cells. However, after 3 weeks in culture the number of large clones (>2 mm) generated by p63+/L514F cells was significantly lower than their wild-type counterparts (Fig 6A). Under clonogenic conditions, the overall mutant population was less proliferative (Supporting Information Fig S10A) consistent with a reduced number of clonogenic cells or with a reduced ability to proliferate under clonogenic conditions. However, no differences in cell proliferation were detected between p63+/L514F mutant and wild-type large clones 3 weeks after plating in spite of a maintained reduction in Fgfr2 protein expression (Supporting Information Fig S10B-C). Accordingly, Fgfr2b−/− keratinocytes had a very similar reduction in the number of large clones (>2 mm) compared to wild-type controls in spite of a similar initial plating efficiency (Fig 6B).