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


Reference:

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. and Ernst, M., 2010. Genetic dissection of differential signaling threshold requirements for the Wnt/β-Catenin pathway in vivo. Plos Genetics, 6 (1), e1000816.

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    Official URL:

    http://dx.doi.org/10.1371/journal.pgen.1000816

    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.

    Details

    Item Type Articles
    CreatorsBuchert, 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. and Ernst, M.
    DOI10.1371/journal.pgen.1000816
    DepartmentsFaculty of Science > Biology & Biochemistry
    Research CentresCentre for Regenerative Medicine
    Publisher Statementjournal.pgen.1000816.pdf: © 2010 Buchert et al. The full text of this article is republished here according to the terms of a Creative Commons Attribution Licence. The article should always be cited as follows: Buchert M, Athineos D, Abud HE, Burke ZD, Faux MC, et al. (2010) Genetic Dissection of Differential Signaling Threshold Requirements for the Wnt/β-Catenin Pathway In Vivo. PLoS Genet 6(1): e1000816. doi:10.1371/journal.pgen.1000816
    RefereedYes
    StatusPublished
    ID Code17980

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