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

Giustina Ferone, Helen A. Thomason, Dario Antonini, Laura De Rosa, Bing Hu, Marica Gemei, Huiqing Zhou, Raffaele Ambrosio, David P. Rice, Dario Acampora, Hans van Bokhoven, Luigi Del Vecchio, Maranke I. Koster, Gianluca Tadini, Bradley Spencer-Dene, Michael Dixon, Jill Dixon, Caterina Missero

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)192-205
Number of pages14
JournalEMBO Molecular Medicine
Volume4
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • AEC syndrome
  • Epidermis
  • FGF signalling
  • P63 knock-in
  • P63 target genes

ASJC Scopus subject areas

  • Molecular Medicine

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