Wwtr1-KO Mouse

Wwtr1, also known as TAZ (transcriptional coactivator with PDZ-binding motif), is a transcriptional co-activator. It is a key component of the Hippo signaling pathway, which is an important tumor-suppressor pathway. Wwtr1 plays significant roles in cell proliferation, stem cell maintenance, and tissue homeostasis. It can integrate signals from multiple upstream signaling pathways, cell-cell interactions, and mechanical forces, then bind to and activate different downstream transcriptional factors [2,3,4,5].

In non-alcoholic steatohepatitis (NASH), hepatocyte TAZ/WWTR1 levels are higher in NASH livers compared to normal or steatotic livers. Silencing of hepatocyte TAZ in murine NASH models prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Hepatocyte-targeted expression of TAZ in a steatosis model promoted 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 vascular cancer, the TAZ-CAMTA1 gene fusion (found in ∼90% of cases) drives the formation of vascular tumors with EHE features. Inhibition of TAZ-CAMTA1 leads to tumor regression. Activated TAZ also drives the formation of EHE-like vascular tumors [6]. Mice deficient in Wwtr1 show clinical features of late-onset Fuchs' endothelial corneal dystrophy, such as reduced corneal endothelial cell (CEnC) density, abnormal CEnC morphology, softer Descemet's membrane, thinner corneas, and impaired CEnC wound healing [7]. In p53-proficient colon cancer cells, oxaliplatin treatment leads to nuclear accumulation of TAZ, and TAZ is required for increased sensitivity to oxaliplatin [8].

In summary, Wwtr1 is crucial in the Hippo signaling pathway, influencing multiple biological processes. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its role in diseases like NASH, EHE, Fuchs' endothelial corneal dystrophy, and in determining chemosensitivity in colon cancer. These models have provided valuable insights into the underlying mechanisms of these diseases, highlighting Wwtr1 as a potential therapeutic target in these disease areas [1,6,7,8].

References:

1. Wang, Xiaobo, Zheng, Ze, Caviglia, Jorge Matias, Schwabe, Robert F, Tabas, Ira. 2016. Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. In Cell metabolism, 24, 848-862. doi:10.1016/j.cmet.2016.09.016. https://pubmed.ncbi.nlm.nih.gov/28068223/

2. Andl, Thomas, Zhou, Linli, Yang, Kun, Kadekaro, Ana Luisa, Zhang, Yuhang. 2017. YAP and WWTR1: New targets for skin cancer treatment. In Cancer letters, 396, 30-41. doi:10.1016/j.canlet.2017.03.001. https://pubmed.ncbi.nlm.nih.gov/28279717/

3. Zanconato, Francesca, Cordenonsi, Michelangelo, Piccolo, Stefano. . YAP/TAZ at the Roots of Cancer. In Cancer cell, 29, 783-803. doi:10.1016/j.ccell.2016.05.005. https://pubmed.ncbi.nlm.nih.gov/27300434/

4. Koo, Ja Hyun, Guan, Kun-Liang. . Interplay between YAP/TAZ and Metabolism. In Cell metabolism, 28, 196-206. doi:10.1016/j.cmet.2018.07.010. https://pubmed.ncbi.nlm.nih.gov/30089241/

5. Totaro, Antonio, Panciera, Tito, Piccolo, Stefano. 2018. YAP/TAZ upstream signals and downstream responses. In Nature cell biology, 20, 888-899. doi:10.1038/s41556-018-0142-z. https://pubmed.ncbi.nlm.nih.gov/30050119/

6. Driskill, Jordan H, Zheng, Yonggang, Wu, Bo-Kuan, Dellinger, Michael, Pan, Duojia. 2021. WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma. In Genes & development, 35, 495-511. doi:10.1101/gad.348221.120. https://pubmed.ncbi.nlm.nih.gov/33766984/

7. Leonard, Brian C, Park, Sangwan, Kim, Soohyun, Raghunathan, Vijay Krishna, Thomasy, Sara M. . Mice Deficient in TAZ (Wwtr1) Demonstrate Clinical Features of Late-Onset Fuchs' Endothelial Corneal Dystrophy. In Investigative ophthalmology & visual science, 64, 22. doi:10.1167/iovs.64.4.22. https://pubmed.ncbi.nlm.nih.gov/37074694/

8. Slaninová, Věra, Heron-Milhavet, Lisa, Robin, Mathilde, Gongora, Céline, Djiane, Alexandre. 2024. The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells. In BMC cancer, 24, 587. doi:10.1186/s12885-024-12316-4. https://pubmed.ncbi.nlm.nih.gov/38741073/