A genetic study of the role of the Wnt/β-catenin signalling in Paneth cell differentiation
A genetic study of the role of the Wnt/β-catenin signalling in Paneth cell differentiation
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DOI：
10.1016/j.ydbio.2008.09.027
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发表时间：
2008-12-15
影响因子：
2.7
通讯作者：
Romagnolo, Beatrice
中科院分区：
文献类型：
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作者：
Andreu, Pauline;Peignon, Gregory;Romagnolo, Beatrice
WNT/β-连环蛋白信号通路在肠上皮细胞的动态平衡中起着关键作用。虽然它在维持尾部细胞室中的作用已被清楚地证明，但它在Paneth细胞命运中的作用尚不清楚。我们进行了遗传学研究，以阐明Wnt/β-catenin途径在Paneth细胞分化中的功能。我们分析了在Wnt/β-catenin途径中具有可诱导的功能获得突变的小鼠，以及具有先前未描述的亚形β-catenin等位基因的小鼠。我们证明，Wnt/β-catenin信号的急性激活诱导了小肠和结肠中Paneth细胞的从头规范，并且由APC突变引起的结肠癌表达了许多与Paneth细胞分化有关的基因。这表明Wnt/β-catenin通路在Paneth细胞分化中起着关键作用。我们还发现，β-连环素基因剂量的轻微减少导致了Paneth细胞分化的一个主要缺陷，但对隐窝的形态发生只有轻微的影响。总体而言，我们的发现表明，决定潘氏细胞命运需要高水平的β-连环蛋白激活，而对β-连环蛋白信号的微调对于正确的潘氏细胞谱系至关重要。(C)2008 Elsevier Inc.保留所有权利。
Wnt/beta-catenin signalling plays a key role in the homeostasis of the intestinal epithelium. Whereas its role in the maintenance of the stern cell compartment has been clearly demonstrated, its role in the Paneth cell fate remains unclear We performed genetic studies to elucidate the functions of the Wnt/beta-catenin pathway in Paneth cell differentiation. We analysed mice with inducible gain-of-function mutations in the Wnt/beta-catenin pathway and mice with a hypomorphic beta-catenin allele that have not been previously described. We demonstrated that acute activation of Wnt/beta-catenin signalling induces de novo specification of Paneth cells in both the small intestine and colon and that colon cancers resulting from Apc mutations expressed many genes involved in Paneth cell differentiation. This suggests a key role for the Wnt/beta-catenin pathway in Paneth cell differentiation. We also showed that a slight decrease in beta-catenin gene dosage induced a major defect in Paneth cell differentiation, but only a modest effect on crypt morphogenesis. Overall, our findings show that a high level of beta-catenin activation is required to determine Paneth cell fate and that fine tuning of beta-catenin signalling is critical for correct Paneth cell lineage. (C) 2008 Elsevier Inc. All rights reserved.