Ankyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock‐in mouse model for AEC syndrome (
p63
+/L514F
) that recapitulates the human disorder. 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. In parallel, a defective stem cell compartment is observed in humans affected by AEC syndrome and in
Fgfr2b
−/−
mice. Restoring
Fgfr2b
expression in
p63
+/L514F
epithelial cells by treatment with FGF7 reactivates downstream mitogen‐activated protein kinase signalling and cell proliferation. These findings establish a functional link between FGF signalling and p63 in the expansion of epithelial progenitor cells and provide mechanistic insights into the pathogenesis of AEC syndrome.
See accompanying article
http://dx.doi.org/10.1002/emmm.201100202...

Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome

10.1002/emmm.201100199