Wwtr1-flox Mouse

Wwtr1, also known as TAZ (transcriptional coactivator with PDZ-binding motif), is a key transcriptional regulator. It is a core component of the Hippo signaling pathway, which is crucial for cell-cell interactions, growth, and tumor-suppression. Dysregulation of this pathway can lead to various diseases. Wwtr1 senses the cell microenvironment's structural and mechanical features and integrates signals from multiple upstream signaling pathways [2,3,4].

In non-alcoholic steatohepatitis (NASH), hepatocyte TAZ/Wwtr1 is significantly higher. Silencing hepatocyte TAZ in murine NASH models prevents or reverses hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Hepatocyte-targeted TAZ expression in a steatosis model promotes NASH features, including fibrosis. Mechanistically, TAZ/TEAD-mediated induction of Indian hedgehog (Ihh) activates fibrogenic genes in hepatic stellate cells [1].

In epithelioid hemangioendothelioma (EHE), a TAZ-CAMTA1 gene fusion occurs in about 90% of cases. TAZ-CAMTA1 expression in endothelial cells drives EHE-like vascular tumors, and its inhibition leads to tumor regression. Activated TAZ resembles TAZ-CAMTA1 in this regard [5].

Mice deficient in Wwtr1 show clinical features of late-onset Fuchs' endothelial corneal dystrophy, such as reduced corneal endothelial cell density, abnormal cell morphology, and impaired wound healing [6].

In summary, Wwtr1 is a vital transcriptional regulator in the Hippo signaling pathway. Gene-knockout mouse models have revealed its role in diseases like NASH, EHE, and Fuchs' endothelial corneal dystrophy. These models help us understand the mechanisms underlying these diseases and may provide potential therapeutic targets.