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First published online 15 April 2009
doi: 10.1242/dev.029140

Development 136, 1727-1739 (2009)
Published by The Company of Biologists 2009
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Notch signaling controls liver development by regulating biliary differentiation

Yiwei Zong1, Archana Panikkar1, Jie Xu1, Aline Antoniou2, Peggy Raynaud2, Frederic Lemaigre2 and Ben Z. Stanger1,*

1 Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 512 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
2 Université Catholique de Louvain and de Duve Institute, Avenue Hippocrate 75/7529, 1200 Brussels, Belgium.

* Author for correspondence (e-mail: bstanger{at}exchange.upenn.edu)

Accepted 17 March 2009

In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. 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, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis.

Key words: Notch, Bile ducts, Liver, Mouse


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© The Company of Biologists Ltd 2009