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

Giustina Ferone1, Helen A Thomason, Dario Antonini

  • 1Fondazione IRCCS SDN, Napoli, Italy.

EMBO Molecular Medicine
|January 17, 2012
PubMed

Insights

A new mouse model for Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome reveals p63 mutations impair skin development by disrupting fibroblast growth factor (FGF) signaling. Restoring FGF signaling in affected cells promotes proliferation, offering insights into AEC pathogenesis.

Area of Science:

  • Developmental Biology
  • Genetics
  • Cell Biology

Background:

  • Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is an autosomal dominant disorder linked to p63 gene mutations.
  • The syndrome causes cleft palate and severe skin defects, impacting ectodermal development.

Purpose of the Study:

  • To generate and characterize a knock-in mouse model for AEC syndrome.
  • To elucidate the molecular mechanisms underlying AEC syndrome pathogenesis, focusing on p63 function and signaling pathways.

Main Methods:

  • Generation of a p63 knock-in mouse model (p63(+/L514F)) mimicking human AEC syndrome.
  • Analysis of progenitor cell expansion, epidermal stem cell compartment, and gene expression (Fgfr2, Fgfr3).
  • Investigating the role of fibroblast growth factor (FGF) signaling by treating cells with FGF7.

Main Results:

  • The p63(+/L514F) mouse model recapitulates human AEC syndrome phenotypes.
  • AEC mutation causes dominant-negative effects on p63, impairing ectodermal progenitor cell expansion and epidermal stem cell function.
  • Impaired FGF signaling due to reduced Fgfr2 and Fgfr3 expression was observed, directly linked to p63 targets.
  • Restoring Fgfr2b expression via FGF7 treatment reactivated MAPK signaling and cell proliferation in affected cells.

Conclusions:

  • A functional link exists between FGF signaling and p63 in epithelial progenitor cell expansion.
  • The study provides mechanistic insights into AEC syndrome pathogenesis, highlighting the critical role of the p63-FGF signaling axis.
  • The mouse model serves as a valuable tool for studying AEC syndrome and related developmental disorders.

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