Endoderm Jagged induces liver and pancreas duct lineage in zebrafish

Danhua Zhang, Keith P. Gates, Lindsey Barske, Guangliang Wang, Joseph J. Lancman, Xin-Xin I. Zeng, Megan Groff, Kasper Wang, Michael J. Parsons, J. Gage Crump and P. Duc Si Dong ()
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Danhua Zhang: Sanford Burnham Prebys Medical Discovery Institute
Keith P. Gates: Sanford Burnham Prebys Medical Discovery Institute
Lindsey Barske: Keck School of Medicine of University of Southern California
Guangliang Wang: Johns Hopkins University School of Medicine
Joseph J. Lancman: Sanford Burnham Prebys Medical Discovery Institute
Xin-Xin I. Zeng: Sanford Burnham Prebys Medical Discovery Institute
Megan Groff: Keck School of Medicine of University of Southern California
Kasper Wang: Keck School of Medicine of University of Southern California
Michael J. Parsons: Johns Hopkins University School of Medicine
J. Gage Crump: Keck School of Medicine of University of Southern California
P. Duc Si Dong: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos with compound homozygous mutations in two Notch ligand genes, jagged1b (jag1b) and jagged2b (jag2b) exhibit a complete loss of canonical Notch activity and duct cells within the liver and exocrine pancreas, whereas hepatocyte and acinar pancreas development is not affected. Further, animal chimera studies demonstrate that wild-type endoderm cells within the liver and pancreas can rescue Notch activity and duct lineage specification in adjacent cells lacking jag1b and jag2b expression. We conclude that these two Notch ligands are directly and solely responsible for all duct lineage specification in these organs in zebrafish. Our study uncovers genes required for lineage specification of the intrahepatopancreatic duct cells, challenges the role of duct cells as progenitors, and suggests a genetic mechanism for ALGS ductal paucity.

Date: 2017
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DOI: 10.1038/s41467-017-00666-6

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