title: Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.
abstract: 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.
authors.affiliation: Fondazione IRCCS SDN, Napoli, Italy.
authors.forename: Giustina
authors.initials: G
authors.lastname: Ferone
authors.forename: Helen A
authors.initials: HA
authors.lastname: Thomason
authors.forename: Dario
authors.initials: D
authors.lastname: Antonini
authors.forename: Laura
authors.initials: L
authors.lastname: De Rosa
authors.forename: Bing
authors.initials: B
authors.lastname: Hu
authors.forename: Marica
authors.initials: M
authors.lastname: Gemei
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.forename: David P
authors.initials: DP
authors.lastname: Rice
authors.forename: Dario
authors.initials: D
authors.lastname: Acampora
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Maranke I
authors.initials: MI
authors.lastname: Koster
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tadini
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Michael
authors.initials: M
authors.lastname: Dixon
authors.forename: Jill
authors.initials: J
authors.lastname: Dixon
authors.forename: Caterina
authors.initials: C
authors.lastname: Missero
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002971:Cleft Lip / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002972:Cleft Palate / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004475:Ectoderm / Q000166:cytology* / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005143:Eyelids / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D005346:Fibroblast Growth Factors