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

Details

Serval ID
serval:BIB_4D30AF1EAC08
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.
Journal
EMBO Molecular Medicine
Author(s)
Ferone G., Thomason H.A., Antonini D., De Rosa L., Hu B., Gemei M., Zhou H., Ambrosio R., Rice D.P., Acampora D., van Bokhoven H., Del Vecchio L., Koster M.I., Tadini G., Spencer-Dene B., Dixon M., Dixon J., Missero C.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
2012
Volume
4
Number
3
Pages
192-205
Language
english
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.
Keywords
Animals, Cell Proliferation, Cleft Lip/genetics, Cleft Lip/metabolism, Cleft Palate/genetics, Cleft Palate/metabolism, Ectoderm/cytology, Ectoderm/metabolism, Ectodermal Dysplasia/genetics, Ectodermal Dysplasia/metabolism, Eye Abnormalities/genetics, Eye Abnormalities/metabolism, Eyelids/abnormalities, Eyelids/metabolism, Female, Fibroblast Growth Factors/metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Signal Transduction, Stem Cells/cytology, Stem Cells/metabolism, Transcription Factors/genetics, Transcription Factors/metabolism, Tumor Suppressor Proteins/genetics, Tumor Suppressor Proteins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
03/05/2012 16:29
Last modification date
20/08/2019 15:02
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