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Fgf10 regulates hepatopancreatic ductal system patterning and differentiation

Nature Genetics volume 39, pages 397–402 (2007)Cite this article

Abstract

During organogenesis, the foregut endoderm gives rise to the many different cell types that comprise the hepatopancreatic system, including hepatic, pancreatic and gallbladder cells, as well as the epithelial cells of the hepatopancreatic ductal system that connects these organs together and with the intestine. However, the mechanisms responsible for demarcating ducts versus organs are poorly understood. Here, we show that Fgf10 signaling from the adjacent mesenchyme is responsible for refining the boundaries between the hepatopancreatic duct and organs. In zebrafish fgf10 mutants, the hepatopancreatic ductal epithelium is severely dysmorphic, and cells of the hepatopancreatic ductal system and adjacent intestine misdifferentiate toward hepatic and pancreatic fates. Furthermore, Fgf10 also functions to prevent the differentiation of the proximal pancreas and liver into hepatic and pancreatic cells, respectively. These data shed light onto how the multipotent cells of the foregut endoderm, and subsequently those of the hepatopancreatic duct, are directed toward different organ fates.

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Figure 1: fgf10 expression in mesenchyme adjacent to the hepatopancreatic ductal system.
Figure 2: fgf10 regulates the morphogenesis of the hepatopancreatic duct and intestinal tube.
Figure 3: fgf10 represses pancreatic and hepatic organ differentiation, as assessed by Prox1 and Hnf4α expression.
Figure 4: fgf10 represses endocrine cell differentiation throughout the hepatopancreatic system.

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Acknowledgements

We thank A. Ayala, S. Waldron and N. Zvenigorodsky for help with the fish; C. Wright, M. Hebrok, M. German, S. Curado, E. Ober, T. Sakaguchi, M. Bagnat and A. Schlegel for discussions and/or critical reading of the manuscript; C. Wright and J. Lewis for antibodies and B. Appel (Vanderbilt University) for the Tg(nkx2.2a:mEGFP) line. P.D.S.D. was supported by the Juvenile Diabetes Research Foundation (32002643) and the Larry L. Hillblom Foundation (2005 1G). C.A.M. was supported by a US National Science Foundation predoctoral fellowship. This work was supported in part by grants from the US National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases), the Juvenile Diabetes Research Foundation and the Packard Foundation (D.Y.R.S.). Requests for materials should be addressed to D.Y.R.S. (didier_stainier@biochem.ucsf.edu).

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Author notes

  1. William Norton

    Present address: Present addresses: ZEN Neurogenetics Group, GSF Forschungszentrum, Neuherberg D-85758, Germany (W.N.) and Department of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA (X.P.).,

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, and the Diabetes Center, University of California, San Francisco, 1550 Fourth Street, San Francisco, 94158, California, USA

    P Duc Si Dong, Chantilly A Munson & Didier Y R Stainier

  2. Developmental Biology Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    William Norton & Carl J Neumann

  3. Vertebrate Development Laboratory, Cancer Research UK, London, WC2 A3PX, UK

    Cecile Crosnier

  4. Department of Biological Sciences, The National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore

    Xiufang Pan & Zhiyuan Gong

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Contributions

P.D.S.D. made the original observation, generated hypotheses, designed experiments, analyzed fgf10 mutants and made the figures; C.A.M. analyzed fgf10 and neuroD expression, performed phenotype assessment and drew the illustration; W.N. and C.J.M. provided fgf10 mutants prior to publication; C.C. provided 2F11 antibodies prior to publication; X.P. and Z.G. provided Tg(lfabp:dsRed) zebrafish prior to publication; D.Y.R.S. oversaw the studies and P.D.S.D., C.A.M. and D.Y.R.S. wrote the manuscript with feedback from the other authors.

Corresponding author

Correspondence to Didier Y R Stainier.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Differential expression of Prox1 and Hfn4α between the hepatopancreatic ducts and organs. (PDF 214 kb)

Supplementary Fig. 2

fgfr2 expression in the endoderm. (PDF 700 kb)

Supplementary Fig. 3

fgf10 mutants lacking the extrapancreatic duct and extrahepatic duct. (PDF 767 kb)

Supplementary Fig. 4

Pdx1 expression in the extrapancreatic duct is not maintained in fgf10 mutants. (PDF 684 kb)

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Dong, P., Munson, C., Norton, W. et al. Fgf10 regulates hepatopancreatic ductal system patterning and differentiation. Nat Genet 39, 397–402 (2007). https://doi.org/10.1038/ng1961

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