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 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.
Buchert
Michael
M
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Australia.
Athineos
Dimitris
D
Abud
Helen E
HE
Burke
Zoe D
ZD
Faux
Maree C
MC
Samuel
Michael S
MS
Jarnicki
Andrew G
AG
Winbanks
Catherine E
CE
Newton
Ian P
IP
Meniel
Valerie S
VS
Suzuki
Hiromu
H
Stacker
Steven A
SA
Näthke
Inke S
IS
Tosh
David
D
Huelsken
Joerg
J
Clarke
Alan R
AR
Heath
Joan K
JK
Sansom
Owen J
OJ
Ernst
Matthias
M
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*
D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin