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

Michael Buchert, Dimitris Athineos, Helen E. Abud, Zoe D. Burke, Maree C. Faux, Michael S. Samuel, Andrew G. Jarnicki, Catherine E. Winbanks, Ian P. Newton, Valerie S. Meniel, Hiromu Suzuki, Steven A. Stacker, Inke S. Nathke, David Tosh, Joerg Huelsken, Alan R. Clarke, Joan K. Heath, Owen J. Sansom, Matthias Ernst

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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/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.

    Original languageEnglish
    Article numbere1000816
    Pages (from-to)-
    Number of pages13
    JournalPLoS Genetics
    Volume6
    Issue number1
    DOIs
    Publication statusPublished - Jan 2010

    Keywords

    • Stem cell differentiation
    • Beta catenin
    • Hepatocellular carcinomas
    • Mouse liver
    • APC gene
    • Intestinal tumorigenesis
    • Head morphogenesis
    • Colorectal cancer
    • Somatic mutations
    • Tumor formation

    Cite this

    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., Nathke, I. S., Tosh, D., Huelsken, J., Clarke, A. R., Heath, J. K., Sansom, O. J., & Ernst, M. (2010). Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. PLoS Genetics, 6(1), -. [e1000816]. https://doi.org/10.1371/journal.pgen.1000816