Notch Signaling regulates formation of the three-dimensional architecture
Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice
Erin E. Sparks 1, Kari A. Huppert 1, Melanie A. Brown 1, M. Kay Washington 2, Stacey S. Huppert 1 *
1Department of Cell and Developmental Biology and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN
2Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
email: Stacey S. Huppert (stacey.huppert@vanderbilt.edu)
*Correspondence to Stacey S. Huppert, Vanderbilt University Medical Center, Center for Stem Cell Biology, 2213 Garland Avenue, 9465 MRB IV, Nashville, TN 37232-0494
Potential conflict of interest: Nothing to report.
fax: 615-322-6645.
Funded by:
National Institutes of Health; Grant Number: RO1-DK078640
Vanderbilt Digestive Disease Research Center; Grant Number: P30-DK058404
Abstract
Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization, we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bipotential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. Although Notch2 has a dominant role in IHBD formation, there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Because changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. Conclusion: There is a threshold requirement for Notch signaling at multiple steps, including IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture. (HEPATOLOGY 2010.)
Received: 29 January 2009; Accepted: 5 November 2009