| Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. | |
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MedLine Citation:
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PMID: 22247000 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-13 |
Journal Detail:
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Title: EMBO molecular medicine Volume: - ISSN: 1757-4684 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101487380 Medline TA: EMBO Mol Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 EMBO Molecular Medicine. |
Affiliation:
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Fondazione IRCCS SDN, Napoli, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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