Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo

Nusse, R. et al. (2010) Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo. PLoS Genetics, 6(1), e1000816. (doi: 10.1371/journal.pgen.1000816)



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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/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-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/beta-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/beta-catenin signaling capacity similar to that in the germline of the Apc(min) mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apc(min) mice arise independently of intestinal tumorigenesis. Together, the present genotype phenotype analysis suggests tissue-specific response levels for the Wnt/beta-catenin pathway that regulate both physiological and pathophysiological conditions.

Item Type:Articles
Additional Information:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Glasgow Author(s) Enlighten ID:Athineos, Mr Dimitris and Sansom, Professor Owen
Authors: Nusse, R., Buchert, M., Athineos, D., Abud, H.E., Burke, Z.D., Faux, M.C., Samuel, M.S., Jarnicki, A.G., Winbanks, C.E., Newton, I.P., Meniel, V.S., Suzuki, H., Stacker, S.A., Näthke, I.S., Tosh, D., Huelsken, J., Clarke, A.R., Heath, J.K., Sansom, O.J., and Ernst, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN (Online):1553-7404
Copyright Holders:© 2010 Buchert et al.
First Published:First published in PLoS Genetics 2010 6(1): e1000816
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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