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Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo
- Source :
- PLoS Genetics, Vol 6, Iss 1, p e1000816 (2010), 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/β-Catenin pathway in vivo ', Plos Genetics, vol. 6, no. 1, e1000816 . https://doi.org/10.1371/journal.pgen.1000816, PLoS Genetics
- Publication Year :
- 2010
- Publisher :
- Public Library of Science (PLoS), 2010.
-
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.<br />Author Summary Germline or somatic mutations in genes are the underlying cause of many human diseases, most notably cancer. Interestingly though, even in situations where every cell of every tissue of an organism carries the same mutation (as is the case for germline mutations), some tissues are more susceptible to the development of disease over time than others. For example, in familial adenomatous polyposis (FAP), affected persons carry different germline mutations in the APC gene and are prone to developing cancers of the colon and the rectum—and, less frequently, cancers in other tissues such as stomach, liver, and bones. Here we utilize a panel of mutant mice with truncating or hypomorphic mutations in the Apc gene, resulting in different levels of activation of the Wnt/β-catenin pathway. Our results reveal that different pathophysiological outcomes depend on different permissive signaling thresholds in embryonic, intestinal, and liver tissues. Importantly, we demonstrate that reducing Wnt pathway activation by 50% is enough to prevent the manifestation of embryonic abnormalities and disease in the adult mouse. This raises the possibility of developing therapeutic strategies that modulate the activation levels of this pathway rather than trying to “repair” the mutation in the gene itself.
- Subjects :
- Male
Cancer Research
Cellular differentiation
medicine.disease_cause
recombinant proteins
Cell Biology/Cell Signaling
Developmental Biology/Pattern Formation
Mice
0302 clinical medicine
Intestinal mucosa
antigen-presenting cells
Intestinal Mucosa
Genetics and Genomics/Genetics of Disease
Cells, Cultured
beta Catenin
Genetics (clinical)
Developmental Biology/Embryology
Mice, Knockout
0303 health sciences
Wnt signaling pathway
LRP5
3. Good health
Intestines
Liver
030220 oncology & carcinogenesis
alleles
Head morphogenesis
Female
carcinogenesis
Research Article
Signal Transduction
Beta-catenin
lcsh:QH426-470
Adenomatous Polyposis Coli Protein
Oncology/Gastrointestinal Cancers
Gastroenterology and Hepatology
Biology
Wnt3 Protein
RC0254
03 medical and health sciences
Genetics
medicine
Animals
Allele
Genetics and Genomics/Cancer Genetics
QH426
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Wnt signaling cascade
Fibroblasts
Embryo, Mammalian
Mice, Inbred C57BL
Wnt Proteins
lcsh:Genetics
developmental signaling
biology.protein
Cancer research
gastrointestinal tract
Carcinogenesis
embryos
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 6
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....0455271e1be66294c79ae57b3e164fbf