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

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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.

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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.


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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.

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Correspondence to Toshio Hirano.

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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)

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

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