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Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

Nature Genetics volume 36, pages 83–87 (2004)Cite this article

Abstract

The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals. The molecular mechanisms that determine the identity of each organ in this complex area are unknown. Hes1 encodes the basic helix-loop-helix protein Hes1 (ref. 1), which represses positive basic helix-loop-helix genes2 such as Neurog3 (ref. 3). Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway4. Hes1 operates as a general negative regulator of endodermal endocrine differentiation5,6, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation7,8. Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome in humans9,10, characterized by poor development of the biliary system11, suggesting that the Notch pathway is also involved in normal biliary development. Here we show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice2 have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts. Biliary epithelium in Hes1−/− mice ectopically expresses the proendocrine gene Neurog3 (refs. 12,13), differentiates into endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts. Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3.

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Figure 1: Semiquantitative RT-PCR analysis of expression of Notch and Hes genes in normal mouse embryos.
Figure 2: Abnormal development of biliary epithelium in Hes1−/− embryos.
Figure 3: Gallbladder agenesis and hypoplasia of extrahepatic bile ducts in E17.5
Figure 4: Lack of Hes1 leads to pancreatic cell-type differentiation and pancreatic morphogenesis in the biliary ducts.
Figure 5: Hes1 represses Neurog3 expression in the developing biliary epithelium.
Figure 6: Ipf1 protein is expressed in the biliary epithelial cells and the pancreas.

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Acknowledgements

We thank M. Nagata, M. Kobayashi, S. Takahashi, Y. Kawachi, T. Yamaoka and M. Itakura for critical discussions and T. Ohto, S. Itoh, N. Kajiwara and R. Hirochika for technical assistance.

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Authors and Affiliations

  1. Department of Child Health, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

    Ryo Sumazaki, Shigemi Isoyama & Akira Matsui

  2. Biological Institute, Faculty of Science, Shizuoka University, Shizuoka, Japan

    Nobuyoshi Shiojiri

  3. Department of Molecular Neurobiology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan

    Masayuki Masu & Kazuko Keino-Masu

  4. Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Mitsujiro Osawa & Hiromitsu Nakauchi

  5. Institute for Virus Research, Kyoto University, Kyoto, Japan

    Ryoichiro Kageyama

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  1. Ryo Sumazaki
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Correspondence to Ryo Sumazaki.

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Sumazaki, R., Shiojiri, N., Isoyama, S. et al. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 36, 83–87 (2004). https://doi.org/10.1038/ng1273

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