Bile duct proliferation in liver-specific Jag1 conditional knockout mice: Effects of gene dosage.

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Bile duct proliferation in

liver-specific Jag1 conditional

knockout mice: Effects of gene dosage.

Kathleen M. Loomes, Pierre Russo, , , Lara Underkoffler, Curtis Glover, Hong Fu, Gridley, Klaus

H. Kaestner, J. Oakey

Published Online: 5 Jan 2007

Abstract

The

Notch signaling pathway is involved in determination of cell fate and control

of cell proliferation in multiple organ systems. Jag1 encodes a ligand

in the Notch pathway and has been identified as the disease-causing gene for

the developmental disorder Alagille syndrome. Evidence from the study of human disease and mouse

models has implicated Jag1 as

having an important role in the development of bile ducts. We

have derived a conditional knockout allele (Jag1loxP)

to study the role of Jag1 and

Notch signaling in liver and bile duct development. We

crossed Jag1loxP

mice with a transgenic line carrying Cre recombinase under the control of the albumin promoter and

-fetoprotein enhancer to

ablate Jag1 in hepatoblasts. The liver-specific

Jag1 conditional knockout mice

showed normal bile duct development. To further

decrease Notch pathway function, we crossed the Jag1 conditional knockout mice with mice carrying the hypomorphic Notch2

allele, and bile duct anatomy remained normal. When Jag1 conditional mice were crossed with

mice carrying the Jag1 null

allele, the adult progeny exhibited striking bile duct proliferation. Conclusion:

These results indicate that Notch signaling in the liver is sensitive to Jag1 gene dosage and suggest a role for

the Notch pathway in postnatal growth and morphogenesis of bile ducts. (HEPATOLOGY

2007.)

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