title: Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo.
abstract: Axin proteins are key negative regulators of the canonical Wnt signal transduction pathway. Although Axin2 null mice are viable, we identified an unusual ENU-induced recessive allele of Axin2, canp, that causes midgestation lethality in homozygotes. We show that the Axin2(canp) mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2(canp) protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2(canp) mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2(canp) mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2(canp) mutant embryos that is associated with the formation of an ectopic tail in some mutants. Treatment of wild-type embryos with an inhibitor of Tankyrase that stabilizes Axin proteins also causes inhibition of Wnt signaling in anterior regions of the embryo and a gain of Wnt signaling in the primitive streak. The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak.
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Lihui
authors.initials: L
authors.lastname: Qian
authors.forename: James P
authors.initials: JP
authors.lastname: Mahaffey
authors.forename: Heather L
authors.initials: HL
authors.lastname: Alcorn
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Anderson
mesh_terms: D000818:Animals; D060466:Axin Protein; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D051379:Mice; D009154:Mutation; D009928:Organ Specificity; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D003598:Cytoskeletal Proteins; D051153:Wnt Proteins