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      Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1

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          Abstract

          The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a ( fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

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          Formation of the digestive system in zebrafish. I. Liver morphogenesis.

          Holly A Field, Elke A. Ober, Tobias Roeser … (2003)
          Despite the essential functions of the digestive system, much remains to be learned about the cellular and molecular mechanisms responsible for digestive organ morphogenesis and patterning. We introduce a novel zebrafish transgenic line, the gutGFP line, that expresses GFP throughout the digestive system, and use this tool to analyze the development of the liver. Our studies reveal two phases of liver morphogenesis: budding and growth. The budding period, which can be further subdivided into three stages, starts when hepatocytes first aggregate, shortly after 24 h postfertilization (hpf), and ends with the formation of a hepatic duct at 50 hpf. The growth phase immediately follows and is responsible for a dramatic alteration of liver size and shape. We also analyze gene expression in the developing liver and find a correlation between the expression of certain transcription factor genes and the morphologically defined stages of liver budding. To further expand our understanding of budding morphogenesis, we use loss-of-function analyses to investigate factors potentially involved in this process. It had been reported that no tail mutant embryos appear to lack a liver primordium, as assessed by gata6 expression. However, analysis of gutGFP embryos lacking Ntl show that the liver is in fact present. We also find that, in these embryos, the direction of liver budding does not correlate with the direction of intestinal looping, indicating that the left/right behavior of these tissues can be uncoupled. In addition, we use the cloche mutation to analyze the role of endothelial cells in liver morphogenesis, and find that in zebrafish, unlike what has been reported in mouse, endothelial cells do not appear to be necessary for the budding of this organ.
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            Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish.

            Johnny He, Po Lu, Q Zou … (2014)
            The liver has high regenerative capacity, but it is not clear whether most biliary cells (particularly larger cholangiocytes) transdifferentiate into hepatocytes in regenerating liver. We investigated how this process might contribute to liver regeneration in zebrafish. Zebrafish transgenic lines were generated using the standard I-SceI meganuclease transgenesis technique. Hepatocytes of the Tg(lfabp:mCherry-NTR)(cq2) animals were ablated by the administration of metronidazole. We investigated transdifferentiation of biliary cells to hepatocytes and expression of markers using whole mount antibody staining, fluorescent in situ hybridization, and Cre/loxP-based genetic lineage tracing analyses. The role of biliary cells in hepatocyte regeneration was explored using zebrafish larvae with defects in biliary cell development. After extreme loss of hepatocytes, nearly all the biliary cells steadily lost their tubular morphology, proliferated, and expressed hepatocyte-specific markers. Cre/loxP-based inducible lineage tracing showed that new hepatocytes mainly arose from transdifferentiation of biliary cells; this process required Notch signaling and, in turn, activation of Sox9b in cholangiocytes. Activation of early endoderm and hepatoblast markers in most of the cholangiocytes indicated that biliary transdifferentiation includes a step of dedifferentiation into a bipotential intermediate. Defects in development of biliary cells impaired hepatocyte regeneration. Using our zebrafish liver regeneration model, we found that biliary cells can transdifferentiate into hepatocytes and are the major contributors to hepatocyte regeneration after extreme hepatocyte loss. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Mesodermal Wnt2b signalling positively regulates liver specification.

              Rob H. Field, Heather Verkade, Elke A. Ober … (2006)
              Endodermal organs such as the lung, liver and pancreas emerge at precise locations along the primitive gut tube. Although several signalling pathways have been implicated in liver formation, so far no single gene has been identified that exclusively regulates liver specification. In zebrafish, the onset of liver specification is marked by the localized endodermal expression of hhex and prox1 at 22 hours post fertilization. Here we used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype: prometheus (prt) mutants exhibit profound, though transient, defects in liver specification. Positional cloning reveals that prt encodes a previously unidentified Wnt2b homologue. prt/wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses show the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signalling. Taken together, these data reveal an unexpected positive role for Wnt signalling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.
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                Author and article information

                Contributors
                Anming Meng: Role: Editor
                Journal
                Journal ID (nlm-ta): J Mol Cell Biol
                Journal ID (iso-abbrev): J Mol Cell Biol
                Journal ID (publisher-id): jmcb
                Title: Journal of Molecular Cell Biology
                Publisher: Oxford University Press
                ISSN (Print): 1674-2788
                ISSN (Electronic): 1759-4685
                Publication date Collection: June 2019
                Publication date (Electronic): 14 November 2018
                Publication date PMC-release: 14 November 2018
                Volume: 11
                Issue: 6
                Pages: 448-462
                Affiliations
                [1 ]MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, China
                [2 ]College of Life Sciences, Southwest University, Chongqing, China
                [3 ]College of Life Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, China
                Author notes

                Ce Gao and Weidong Huang authors contributed equally to this work.

                Correspondence to: Jinrong Peng, E-mail: pengjr@ 123456zju.edu.cn
                Article
                Publisher ID: mjy068
                DOI: 10.1093/jmcb/mjy068
                PMC ID: 6604603
                PubMed ID: 30428031
                SO-VID: ede68956-b811-47ec-9f5a-8b767d5349d4
                Copyright © © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                Date received : 01 October 2018
                Date accepted : 13 November 2018
                Page count
                Pages: 15
                Funding
                Funded by: Ministry of Science and Technology of China 10.13039/501100002855
                Award ID: 2015CB942802
                Award ID: 2017YFA0504501
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31330050
                Award ID: 31571495
                Categories
                Subject: Original Article

                Keywords: liver development,hepatopancreatic duct (hpd),hhex,pdx1,cdx1b
                Data availability:
                Keywords: liver development, hepatopancreatic duct (hpd), hhex, pdx1, cdx1b

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