Wnt/β-Catenin is essential for intestinal Homeostasis and maintenance of intestinal stem cells

被引:492
作者
Fevr, Tea
Robine, Sylvie
Louvard, Daniel
Huelsken, Joerg
机构
[1] Swiss Inst Expt Canc Res, Ecole Polytech Fed Lausanne, CH-1066 Epalinges, Switzerland
[2] CNRS, Inst Curie, UMR 144, F-75248 Paris 05, France
关键词
D O I
10.1128/MCB.01034-07
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. beta-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible beta-catenin gene ablation in adult mice. Block of Wnt/beta-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of beta-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/beta-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.
引用
收藏
页码:7551 / 7559
页数:9
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