![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
Abstract
The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β-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 β-catenin gene ablation in adult mice. Block of Wnt/β-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 β-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/β-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.
SUPPLEMENTAL MATERIAL
We are grateful to S. Duboux and J. Bamat for technical assistance; A. Trumpp, M. Bettess, and J. Gordon for antibodies; O. Hagenbuchle and S. Wicker for Affymetrix gene chip hybridization; F. Naef and F. Parisi for bioinformatical analysis; M. Bacac for advice with LCM; and A. D. Durham for proofreading.
T.F. and J.H. were supported in part by the Swiss League against Cancer (OCS 01838-02-2006), the SNF (3100AO-104209), and the Swiss NCCR in Molecular Oncology.