Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.
Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.
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DOI：
10.1002/emmm.201100199
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发表时间：
2012-03
影响因子：
11.1
通讯作者：
Missero, Caterina
中科院分区：
文献类型：
--
作者：
Ferone, Giustina;Thomason, Helen A.;Antonini, Dario;De Rosa, Laura;Hu, Bing;Gemei, Marica;Zhou, Huiqing;Ambrosio, Raffaele;Rice, David P.;Acampora, Dario;van Bokhoven, Hans;Del Vecchio, Luigi;Koster, Maranke I.;Tadini, Gianluca;Spencer-Dene, Bradley;Dixon, Michael;Dixon, Jill;Missero, Caterina
唇腭裂综合征是由转录因子p63基因突变引起的常染色体显性遗传性疾病，以腭裂和皮肤严重缺陷为特征。在这里，我们报告了AEC综合征(p63+/L514F)敲入小鼠模型的产生，该模型概括了人类的疾病。AEC突变通过影响外胚层发育过程中祖细胞的扩增，对野生型p63发挥选择性显性-负性作用，导致表皮干细胞亚群缺陷。这些表型与成纤维细胞生长因子(成纤维细胞生长因子)信号的损伤有关，这是由于直接的p63靶基因FGFR2和FGFR3的表达减少所致。同时，在受急性血管内皮细胞综合征影响的人类和FGFR2b−/−小鼠中也观察到有缺陷的干细胞室。通过Fgf7处理恢复p63+/L514F上皮细胞中FGFR2b的表达，重新激活下游丝裂原活化蛋白激酶信号转导和细胞增殖。这些发现建立了成纤维细胞生长因子信号和p63在上皮祖细胞增殖中的功能联系，并为AEC综合征的发病机制提供了机制上的见解。
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.
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影响因子：
3.7
作者：
Lopardo T;Lo Iacono N;Marinari B;Giustizieri ML;Cyr DG;Merlo G;Crosti F;Costanzo A;Guerrini L
通讯作者：
Guerrini L
影响因子：
23.9
作者：
Fuchs E
通讯作者：
Fuchs E
影响因子：
64.8
作者：
Mills, AA;Zheng, BH;Bradley, A
通讯作者：
Bradley, A
影响因子：
2
作者：
Julapalli, Meena R.;Scher, Richard K.;Bree, Alanna F.
通讯作者：
Bree, Alanna F.
影响因子：
15.9
作者：
Mandinova, Anna;Kolev, Vihren;Dotto, G. Paolo
通讯作者：
Dotto, G. Paolo