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Mesodermal Wnt2b signalling positively regulates liver specification

Abstract

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 formation1,2, 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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Figure 1: Formation of hepatoblasts and differentiating hepatocytes is specifically affected in prt mutant embryos.
Figure 2: Transplantation of rhodamine-labelled wild-type cells into homozygous prt mutant embryos reveals that prt functions cell-non-autonomously in promoting liver formation.
Figure 3: prt encodes Wnt2bb.
Figure 4: wnt2bb expression is dynamic during organogenesis stages.

References

  1. Lemaigre, F. & Zaret, K. S. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr. Opin. Genet. Dev. 14, 582–590 (2004)

    Article  CAS  Google Scholar 

  2. Zhao, R. & Duncan, S. A. Embryonic development of the liver. Hepatology 41, 956–967 (2005)

    Article  CAS  Google Scholar 

  3. Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Holtzinger, A. & Evans, T. Gata4 regulates the formation of multiple organs. Development 132, 4005–4014 (2005)

    Article  CAS  Google Scholar 

  5. Field, H. A., Ober, E. A., Roeser, T. & Stainier, D. Y. Formation of the digestive system in zebrafish. I. Liver morphogenesis. Dev. Biol. 253, 279–290 (2003)

    Article  CAS  Google Scholar 

  6. Le Douarin, N. M. An experimental analysis of liver development. Med. Biol. 53, 427–455 (1975)

    CAS  Google Scholar 

  7. Fukuda-Taira, S. Hepatic induction in the avian embryo: specificity of reactive endoderm and inductive mesoderm. J. Embryol. Exp. Morphol. 63, 111–125 (1981)

    CAS  PubMed  Google Scholar 

  8. Jung, J., Zheng, M., Goldfarb, M. & Zaret, K. S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284, 1998–2003 (1999)

    Article  CAS  Google Scholar 

  9. Rossi, J. M., Dunn, N. R., Hogan, B. L. & Zaret, K. S. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev. 15, 1998–2009 (2001)

    Article  CAS  PubMed Central  Google Scholar 

  10. Ng, J. K. et al. The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development 129, 5161–5170 (2002)

    CAS  PubMed  Google Scholar 

  11. Landesman, Y. & Sokol, S. Y. Xwnt-2b is a novel axis-inducing Xenopus Wnt, which is expressed in embryonic brain. Mech. Dev. 63, 199–209 (1997)

    Article  CAS  Google Scholar 

  12. Lewis, J. L. et al. Reiterated Wnt signaling during zebrafish neural crest development. Development 131, 1299–1308 (2004)

    Article  CAS  Google Scholar 

  13. Jasoni, C., Hendrickson, A. & Roelink, H. Analysis of chicken Wnt-13 expression demonstrates coincidence with cell division in the developing eye and is consistent with a role in induction. Dev. Dyn. 215, 215–224 (1999)

    Article  CAS  Google Scholar 

  14. Zakin, L. D. et al. Structure and expression of Wnt13, a novel mouse Wnt2 related gene. Mech. Dev. 73, 107–116 (1998)

    Article  CAS  Google Scholar 

  15. Matsumoto, K., Yoshitomi, H., Rossant, J. & Zaret, K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294, 559–563 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Zorn, A. M., Butler, K. & Gurdon, J. B. Anterior endomesoderm specification in Xenopus by Wnt/β-catenin and TGF-β signalling pathways. Dev. Biol. 209, 282–297 (1999)

    Article  CAS  Google Scholar 

  17. Suksaweang, S. et al. Morphogenesis of chicken liver: identification of localized growth zones and the role of β-catenin/Wnt in size regulation. Dev. Biol. 266, 109–122 (2004)

    Article  CAS  PubMed Central  Google Scholar 

  18. Hussain, S. Z. et al. Wnt impacts growth and differentiation in ex vivo liver development. Exp. Cell Res. 292, 157–169 (2004)

    Article  CAS  Google Scholar 

  19. Monga, S. P., Pediaditakis, P., Mule, K., Stolz, D. B. & Michalopoulos, G. K. Changes in WNT/β-catenin pathway during regulated growth in rat liver regeneration. Hepatology 33, 1098–1109 (2001)

    Article  CAS  PubMed Central  Google Scholar 

  20. Bort, R., Martinez-Barbera, J. P., Beddington, R. S. & Zaret, K. S. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 131, 797–806 (2004)

    Article  CAS  Google Scholar 

  21. Sosa-Pineda, B., Wigle, J. T. & Oliver, G. Hepatocyte migration during liver development requires Prox1. Nature Genet. 25, 254–255 (2000)

    Article  CAS  Google Scholar 

  22. Finley, K. R., Tennessen, J. & Shawlot, W. The mouse secreted frizzled-related protein 5 gene is expressed in the anterior visceral endoderm and foregut endoderm during early post-implantation development. Gene Expr. Patterns 3, 681–684 (2003)

    Article  CAS  Google Scholar 

  23. Pilcher, K. E. & Krieg, P. A. Expression of the Wnt inhibitor, sFRP5, in the gut endoderm of Xenopus. Gene Expr. Patterns 2, 369–372 (2002)

    Article  CAS  Google Scholar 

  24. Horne-Badovinac, S., Rebagliati, M. & Stainier, D. Y. A cellular framework for gut-looping morphogenesis in zebrafish. Science 302, 662–665 (2003)

    Article  ADS  CAS  Google Scholar 

  25. Roberts, D. J., Smith, D. M., Goff, D. J. & Tabin, C. J. Epithelial-mesenchymal signaling during the regionalization of the chick gut. Development 125, 2791–2801 (1998)

    CAS  PubMed  Google Scholar 

  26. Wells, J. M. & Melton, D. A. Early mouse endoderm is patterned by soluble factors from adjacent germ layers. Development 127, 1563–1572 (2000)

    CAS  PubMed  Google Scholar 

  27. Kumar, M., Jordan, N., Melton, D. & Grapin-Botton, A. Signals from lateral plate mesoderm instruct endoderm toward a pancreatic fate. Dev. Biol. 259, 109–122 (2003)

    Article  CAS  Google Scholar 

  28. Kusserow, A. et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature 433, 156–160 (2005)

    Article  ADS  CAS  Google Scholar 

  29. McBride, H. J., Fatke, B. & Fraser, S. E. Wnt signaling components in the chicken intestinal tract. Dev. Biol. 256, 18–33 (2003)

    Article  CAS  Google Scholar 

  30. Theodosiou, N. A. & Tabin, C. J. Wnt signaling during development of the gastrointestinal tract. Dev. Biol. 259, 258–271 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the members of the Stainier laboratory for their support during the screen; A. Ayala, S. Waldron and N. Zvenigorodsky for expert help with the fish; L. Trinh, S.-W. Jin, H. Knaut and J.-P. Vincent for discussions and critical readings of the manuscript; S. Pleasure for providing a Prox1 antibody before commercialization; and R. Dorsky for providing Tg(hsΔTcf3-GFP). E.A.O. was supported by the UCSF Liver Center through an NIH pilot feasibility grant, and H.V. by a long-term fellowship of the Human Frontier Science Program. This work was supported in part by grants from the NIH (NIDDK) and the Packard Foundation to D.Y.R.S.

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Correspondence to Elke A. Ober or Didier Y. R. Stainier.

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The prt/wnt2bb sequence is deposited in GenBank under accession number DQ231559. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains the Supplementary Methods and Supplementary Figure Legends. (DOC 55 kb)

Supplementary Figure 1

Schematic of the phylogenetic relationship between zebrafish , mouse, rat and human Wnt2 and Wnt2b genes. (JPG 22 kb)

Supplementary Figure 2

Linking liver formation and Wnt2bb to canonical Wnt signaling. (JPG 101 kb)

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Ober, E., Verkade, H., Field, H. et al. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442, 688–691 (2006). https://doi.org/10.1038/nature04888

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