A re-evaluation of two key reagents for in vivo studies of Wnt signaling

Abstract

Conditional mutations and transcription-based reporters are important new tools for exploring the dynamic functions of biological pathways in vivo. While studying the role of the Wnt signaling pathway in cartilage, we observed that the β-catenin-dependent reporter TOPGAL was expressed in chondrocytes in which β-catenin was conditionally inactivated using a Col2a1::cre driver. Here we show that in these embryos recombination is complete and full-length β-catenin protein is absent in chondrocytes. Although a null allele in this context, the recombined β-catenin locus produces a stable transcript that encodes a truncated protein. The truncated protein alone fails to activate TOPFLASH, but strongly potentiates reporter activity in the presence of expressed β-catenin or Tcf4. Together, these data show that each mouse model exhibits specific undesirable properties, findings that strongly suggest the need for specific standards to ensure proper validation of this new generation of genetic tools.