title: Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchert
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.forename: Helen E
authors.initials: HE
authors.lastname: Abud
authors.forename: Zoe D
authors.initials: ZD
authors.lastname: Burke
authors.forename: Maree C
authors.initials: MC
authors.lastname: Faux
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jarnicki
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Meniel
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Inke S
authors.initials: IS
authors.lastname: Näthke
authors.forename: David
authors.initials: D
authors.lastname: Tosh
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology / Q000254:growth & development; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice / Q000196:embryology / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin