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) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. 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 processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. 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 cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, 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 EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.

Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion

“…slc39a6 , wnt4a , and esrra ) was observed. The latter group may be of considerable interest considering recent studies implicating zinc as a regulator of the ectoderm-mesenchyme transition (EMT) during zebrafish gastrulation and human cancer [42,43]. …”

“…Spatial and temporal specificity of target gene transactivation is believed to be controlled by expression of cofactors interacting with Hnf4a. Transcription of hnf4a can be repressed by Snai1a (Snail, snail homolog 1a ( Drosophila )) [55], which has been shown in zebrafish to respond an increase in cellular labile Zn 2+ concentration by nuclearisation and repression of target genes [43]. Hence, the early increase in hnf4a expression is plausibly a result of a reduced inhibition by Snail, as it is likely that the sudden depletion of zinc from the water would reduce the concentration of labile Zn 2+ in the gill cells.…”

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

“…4a). Expression of another zinc transporter, Zip6, an ortholog of zebrafish LIV1, was examined since STAT3, a downstream signal transducer of IL-6, was reported to induce LIV1 (Yamashita et al 2004). However, no significant change in Zip6 mRNA expression was observed under restraint stress (Fig.…”

“…Zinc movement through zinc transporter LIV1 plays a crucial role in zebrafish gastrula organizer cells (Yamashita et al 2004). In dendritic cells, zinc movement caused by down-regulation of zinc importer Zip6 and up-regulation of zinc exporter ZnT-1 was involved in the maturation of dendritic cells (Kitamura et al 2006).…”

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

“…This is characterized by break-down of cell junctions and loss of cell polarity, rendering epithelial cells more motile and invasive (Thiery, 2002). EMT has important roles during development (Yamashita et al, 2004) and in cancer, where it initiates metastasis. A critical step of EMT is the loss of type I cadherins that maintain stable cell-cell contacts (Perl et al, 1998).…”