Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer

Abstract

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs1. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis1,2. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes3,4,5,6. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression7,8,9. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells10. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein11,12,13, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT1,2,14,15. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Zinc transporter LIV1 is a target of STAT3 in zebrafish gastrula organizer cells.
Figure 2: Disruption of gastrulation movement in LIV1 morphants.
Figure 3: Dependence of cell-autonomous role of STAT3 in gastrulation movements on LIV1 activity.
Figure 4: LIV1, STAT3 and Snail are essential for EMT of zebrafish gastrula organizer cells.

References

  1. Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002)

    CAS  Article  Google Scholar 

  2. Savagner, P. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 23, 912–923 (2001)

    CAS  Article  Google Scholar 

  3. Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997)

    ADS  CAS  Article  Google Scholar 

  4. Bromberg, J. & Darnell, J. E. Jr The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000)

    CAS  Article  Google Scholar 

  5. Hirano, T., Ishihara, K. & Hibi, M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548–2556 (2000)

    CAS  Article  Google Scholar 

  6. Kamimura, D. & Hirano, T. in Signal Transducers and Activators of Transcription (STATs): Activation and Biology (eds Sehgal, P. B., Levy, D. E. & Hirano, T.) 155–175 (Kluwer Academic, Dordrecht, 2003)

    Book  Google Scholar 

  7. Sano, S. et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668 (1999)

    CAS  Article  Google Scholar 

  8. Silver, D. L. & Montell, D. J. Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107, 831–841 (2001)

    CAS  Article  Google Scholar 

  9. Yamashita, S. & Hirano, T. in Signal Transducers and Activators of Transcription (STATs): Activation and Biology (eds Sehgal, P. B., Levy, D. E. & Hirano, T.) 595–607 (Kluwer Academic, Dordrecht, 2003)

    Book  Google Scholar 

  10. Yamashita, S. et al. Stat3 controls cell movements during zebrafish gastrulation. Dev. Cell 2, 363–375 (2002)

    CAS  Article  Google Scholar 

  11. Manning, D. L., Daly, R. J., Lord, P. G., Kelly, K. F. & Green, C. D. Effects of oestrogen on the expression of a 4.4 kb mRNA in the ZR-75-1 human breast cancer cell line. Mol. Cell. Endocrinol. 59, 205–212 (1988)

    CAS  Article  Google Scholar 

  12. Manning, D. L. et al. Oestrogen-regulated genes in breast cancer: association of pLIV1 with lymph node involvement. Eur. J. Cancer 30A, 675–678 (1994)

    CAS  Article  Google Scholar 

  13. Taylor, K. M., Morgan, H. E., Johnson, A., Hadley, L. J. & Nicholson, R. I. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem. J. 375, 51–59 (2003)

    CAS  Article  Google Scholar 

  14. Batlle, E. et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biol. 2, 84–89 (2000)

    CAS  Article  Google Scholar 

  15. Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000)

    ADS  CAS  Article  Google Scholar 

  16. Taylor, K. M. & Nicholson, R. I. The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim. Biophys. Acta 1611, 16–30 (2003)

    CAS  Article  Google Scholar 

  17. Fukada, T. et al. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5, 449–460 (1996)

    CAS  Article  Google Scholar 

  18. Nasevicius, A. & Ekker, S. C. Effective targeted gene ‘knockdown’ in zebrafish. Nature Genet. 26, 216–220 (2000)

    CAS  Article  Google Scholar 

  19. Kozlowski, D. J. & Weinberg, E. S. Photoactivatable (caged) fluorescein as a cell tracer for fate mapping in the zebrafish embryo. Methods Mol. Biol. 135, 349–355 (2000)

    CAS  PubMed  Google Scholar 

  20. Dominguez, D. et al. Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol. Cell. Biol. 23, 5078–5089 (2003)

    CAS  Article  Google Scholar 

  21. Van Doren, M. et al. Fear of intimacy encodes a novel transmembrane protein required for gonad morphogenesis in Drosophila. Development 130, 2355–2364 (2003)

    CAS  Article  Google Scholar 

  22. Thisse, C., Thisse, B., Schilling, T. F. & Postlethwait, J. H. Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos. Development 119, 1203–1215 (1993)

    CAS  PubMed  Google Scholar 

  23. Thisse, C., Thisse, B. & Postlethwait, J. H. Expression of snail2, a second member of the zebrafish snail family, in cephalic mesendoderm and presumptive neural crest of wild-type and spadetail mutant embryos. Dev. Biol. 172, 86–99 (1995)

    CAS  Article  Google Scholar 

  24. Solnica-Krezel, L., Stemple, D. L. & Driever, W. Transparent things: cell fates and cell movements during early embryogenesis of zebrafish. Bioessays 17, 931–939 (1995)

    CAS  Article  Google Scholar 

  25. Blanco, M. J. et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241–3246 (2002)

    CAS  Article  Google Scholar 

  26. Bowman, T., Garcia, R., Turkson, J. & Jove, R. STATs in oncogenesis. Oncogene 19, 2474–2488 (2000)

    CAS  Article  Google Scholar 

  27. Ciruna, B. & Rossant, J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev. Cell 1, 37–49 (2001)

    CAS  Article  Google Scholar 

  28. Peinado, H., Quintanilla, M. & Cano, A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J. Biol. Chem. 278, 21113–21123 (2003)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank A. G. De Herreros for the pGL3-E-cadh promoter plasmid and pcDNA3-mm snail-HA plasmid, and many colleagues for providing reagents. We also thank R. Masuda and A. Kubota for secretarial assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Toshio Hirano.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Primary structure of zebrafish LIV1. (PDF 192 kb)

Supplementary Figure 2

Independence of non-cell-autonomous role of STAT3 in gastrulation movements on LIV1 activity. (PDF 56 kb)

Supplementary Figure Legends (DOC 23 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yamashita, S., Miyagi, C., Fukada, T. et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429, 298–302 (2004). https://doi.org/10.1038/nature02545

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02545

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing