title: A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias.
abstract: The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the DeltaNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasome-mediated DeltaNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.
authors.affiliation: Department of Dermatology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Barbara
authors.initials: B
authors.lastname: Marinari
authors.forename: Nadia
authors.initials: N
authors.lastname: Lo Iacono
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Botti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giunta
authors.forename: Giulia
authors.initials: G
authors.lastname: Spallone
authors.forename: Giulia
authors.initials: G
authors.lastname: Garaffo
authors.forename: Emma
authors.initials: E
authors.lastname: Vernersson-Lindahl
authors.forename: Giorgio
authors.initials: G
authors.lastname: Merlo
authors.forename: Alea A
authors.initials: AA
authors.lastname: Mills
authors.forename: Costanza
authors.initials: C
authors.lastname: Ballarò
authors.forename: Stefano
authors.initials: S
authors.lastname: Alemà
authors.forename: Sergio
authors.initials: S
authors.lastname: Chimenti
authors.forename: Luisa
authors.initials: L
authors.lastname: Guerrini
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004476:Ectodermal Dysplasia; D005786:Gene Expression Regulation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C109803:IRF6 protein, human; C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins