Abstract

We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAP^KO mice, resulting in YAP/TAZ double knock out (DKO) and YAP^KO with TAZ heterozygosity (YAP^KO TAZ^HET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA-sequencing.

DKO mice were embryonic lethal, but their livers were similar to YAP^KO, suggesting an extrahepatic cause of death. Male YAP^KO TAZ^HET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAP^KO TAZ^HETfemales survived and were phenotypically similar to YAP^KO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened hepatocellular injury. TAZ heterozygosity in YAP^KO impacted expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.