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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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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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.
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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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DOI: https://doi.org/10.1038/ng1961