Laura Molina, MD, PhD

Travel Award
$1,500

University of Pittsburgh

Yap and Taz are both required to form a stable bile duct network in mice

Mentor: Kari Nejak-Bowen, PhD, MBA

Our team at the University of Pittsburgh has studied two related proteins, YAP and TAZ, which regulate how bile duct cells in the liver develop their identity. We and others have shown that YAP helps bile ducts form a 3D network for bile transport from the liver to the intestines. When we prevented mouse livers from expressing YAP during development, we prevented bile ducts from forming correctly, causing liver disease like Alagille Syndrome and other developmental disorders affecting children. In this study, we showed that the quantity of genetic material encoding for YAP and TAZ together has an impact on bile duct formation. When we completely disrupted the expression of TAZ, but left normal YAP expression, bile ducts formed correctly. When we disrupted half of both YAP and TAZ expression, bile ducts still formed correctly. However, when we completely disrupted TAZ expression and half of YAP expression, the bile ducts formed incompletely during development and started to gradually disappear over the first few months.

The smallest bile ducts were lost first and disappeared first from the edges of the liver and then into the center. This means that while YAP is a main driver of bile duct formation, there needs to be a minimum quantity of both YAP and TAZ for this process to complete normally. These mice develop cholestatic liver disease, similar to Alagille syndrome, primary biliary cirrhosis, and

drug-induced liver injury, among others. We propose that the function of YAP and TAZ can impact the severity of biliary disease and might explain some of the variation in disease course among patients. Further study is needed to understand how YAP and TAZ interact with each other to regulate bile duct formation and how they may be altered in human liver disease.