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Genetic dissection of differential signaling threshold requirements for the Wnt/beta-Catenin pathway in vivo

Buchert, Michael, Athineos, Dimitris, Abud, Helen E., Burke, Zoe D., Faux, Maree C., Samuel, Michael S., Jarnicki, Andrew G., Winbanks, Catherine E., Newton, Ian P, Meniel, Valerie, Suzuki, Hiromu, Stacker, Steven A., Näthke, Inke S., Tosh, David, Huelsken, Joerg, Clarke, Alan Richard, Heath, Joan K., Sansom, Owen J. and Ernst, Matthias 2010. Genetic dissection of differential signaling threshold requirements for the Wnt/beta-Catenin pathway in vivo. PLOS Genetics 6 (1) , e1000816. 10.1371/journal.pgen.1000816

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Abstract

Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/β-catenin pathway, we challenged the allele combinations by genetically restricting intracellular β-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/β-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/β-catenin signaling capacity similar to that in the germline of the Apcmin mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apcmin mice arise independently of intestinal tumorigenesis. Together, the present genotype–phenotype analysis suggests tissue-specific response levels for the Wnt/β-catenin pathway that regulate both physiological and pathophysiological conditions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: PLOS
ISSN: 1553-7390
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 02:05
URI: http://orca.cf.ac.uk/id/eprint/8906

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