Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
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 intra...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2800045?pdf=render |
| _version_ | 1818290059262033920 |
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| author | 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 Näthke David Tosh Joerg Huelsken Alan R Clarke Joan K Heath Owen J Sansom Matthias Ernst |
| author_facet | 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 Näthke David Tosh Joerg Huelsken Alan R Clarke Joan K Heath Owen J Sansom Matthias Ernst |
| author_sort | Michael Buchert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T02:22:09Z |
| format | Article |
| id | doaj.art-c8728f803cb245d0b4062cdd15c9a522 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T02:22:09Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-c8728f803cb245d0b4062cdd15c9a5222022-12-22T00:02:44ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042010-01-0161e100081610.1371/journal.pgen.1000816Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.Michael BuchertDimitris AthineosHelen E AbudZoe D BurkeMaree C FauxMichael S SamuelAndrew G JarnickiCatherine E WinbanksIan P NewtonValerie S MenielHiromu SuzukiSteven A StackerInke S NäthkeDavid ToshJoerg HuelskenAlan R ClarkeJoan K HeathOwen J SansomMatthias ErnstContributions 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.http://europepmc.org/articles/PMC2800045?pdf=render |
| spellingShingle | 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 Näthke David Tosh Joerg Huelsken Alan R Clarke Joan K Heath Owen J Sansom Matthias Ernst Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. PLoS Genetics |
| title | Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. |
| title_full | Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. |
| title_fullStr | Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. |
| title_full_unstemmed | Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. |
| title_short | Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. |
| title_sort | genetic dissection of differential signaling threshold requirements for the wnt beta catenin pathway in vivo |
| url | http://europepmc.org/articles/PMC2800045?pdf=render |
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