TAZ-inactivation partly compensates the phenotype caused by YAP knockdown in livers of YAP/TAZ-deficient mice

The transcriptional co-activators yes-associated protein (YAP) and its paralogue WW domain containing transcription regulator 1 (WWTR1; syn: TAZ) are the two major effectors of the Hippo pathway, which plays a central role in many physiological processes including fibrosis and carcinogenesis. Pharmacological inhibition of the Hippo/YAP/TAZ axis may represent a promising tool for patients with chronic liver diseases and liver cancer. For this, a comprehensive and comparative biological characterization of both factors is needed to decipher their exclusive and common properties in normal and diseased livers.

To examine the impact of YAP- and/or TAZ- deficiency on liver homeostasis, we crossed Alb-Cre mice with animals carrying floxed YAP and TAZ genes (YAPfl/fl, TAZfl/fl)1 to generate liver cell-specific deletions of YAP (YAPKO) or TAZ (TAZKO) as well as mice lacking both proteins (YAPKO/TAZKO). The efficient gene deletion was confirmed on protein and mRNA levels. Surprisingly, livers of 10 weeks old YAPKO male mice were significantly bigger than wildtype, TAZKO, and YAPKO/TAZKO (both, absolute liver weight and liver/body ratio). Serum derived from YAPKO and YAPKO/TAZKO, but not from wildtype and TAZKO animals, showed markedly higher levels of liver damage markers in males and females (ALT: up to 792 U/L; AST: up to 867 U/L). In addition, only in YAPKO and YAPKO/TAZKO liver tissues, pronounced necrotic areas were detected; however, the size and number of these lesions was significantly smaller in double knockout tissues compared to liver lacking YAP. Gomori silver and Sirius Red stains revealed the development of severe fibrosis only in YAPKO and YAPKO/TAZKO livers, again the phenotype was diminished in YAPKO/TAZKO compared to YAPKO tissues.

These data illustrate that YAP has a more profound effect on liver homeostasis than TAZ. Surprisingly, the combined knockout of YAP and TAZ doesn't cause additive or synergistic effects compared with YAP-deficient mice. Instead, TAZ-deficiency partly compensates the phenotype caused by the inactivation of YAP with regard to liver damage and fibrosis. These data indicate that YAP and TAZ facilitate distinct biological features and that YAP-directed therapies does not interfere with TAZ activity.

References:

1. Das T, Safferling K, Rausch S, et al. A molecular mechanotransduction pathway regulates collective migration of epithelial cells. Nat Cell Biol 2015;17:276 – 87.