The role of notch signaling in bile duct development and disease / Yiwei Zong.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Zong, Yiwei.

Contributor:

Stanger, Ben Z., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

xii, 162 pages : illustrations ; 29 cm

Production:

2011.

Summary:

The mammalian biliary system, consisting of the intrahepatic and extrahepatic bile ducts, is responsible for transporting bile from the liver to the intestine. Bile duct dysfunction, as is seen in some congenital biliary diseases such as Alagille syndrome and biliary atresia, can lead to the accumulation of bile in the liver, preventing the excretion of detoxification products and ultimately leading to liver damage. Development of bile ducts requires coordinated cell-cell interactions, resulting in the regulation of cell differentiation and morphogenesis. Notch signaling is required for normal bile duct formation, but its mode of action has been unclear. This thesis shows that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. A detailed in vivo analysis of Notch function during liver development was performed by blocking or activating core components of the pathway at distinct developmental stages. The results demonstrate that Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, ectopic Notch signaling in adult hepatocytes also causes them to adopt a biliary fate through a stepwise process of reprogramming. Conversely, loss of Notch signaling in adult liver results in a failure of bile duct proliferation following toxin-mediated injury, suggesting that Notch signaling regulates liver injury response. Taken together, these results suggest that Notch acts by coordinating biliary differentiation and morphogenesis, and is critical to the biliary identity. The knowledge gained from this thesis will provide novel insights into the mechanisms of liver development and disease.

Notes:

Adviser: Ben Z. Stanger.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2011.

Includes bibliographical references.