期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2011
卷号：108
期号：21
页码：8692-8697
DOI：10.1073/pnas.1100328108
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 Axin2canp mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2canp protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2canp mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2canp mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2canp 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.
