The non-redundant nature of the Axin2 regulatory network in the canonical Wnt signaling pathway

Abstract

Axin is one of two essential scaffolds in the canonical Wnt pathway that converts signals at the plasma membrane to signals inhibiting the degradation of {beta}-catenin, leading to its accumulation and specific gene activation. In vertebrates there are two forms of Axin, Axin1 and Axin2, which are similar at the protein level and genetically redundant. We show here that differential regulation of the two genes on the transcriptional and proteostatic level confers robustness and differential responsiveness that can be used in tissue specific regulation. Such subtle features may distinguish other redundant gene pairs that are commonly found in vertebrates through gene knockout experiments. Significance StatementThe mystery of two functionally redundant Axin genes in all vertebrates are can now be explained by the demonstration that they form a nested proteostatic and transcriptional feedback system that confers regulatory options in different developmental settings, a form of dynamic versatility that may explain the widespread occurrence of closely related seemingly redundant genes with similar functions.