Loss of taz after yap deletion severely impairs foregut development and worsens cholestatic hepatocellular injury

Background: We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAP(KO)) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAP(KO) hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity. Methods: 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 knockout (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. Results: 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(HET) females survived and were phenotypically similar to YAP(KO) mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAP(KO) impacted the 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. Conclusions: YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAP(KO) livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.