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

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs(1). EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis(1,2). 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 processes(3-6). STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression(7-9). 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 cells(10). The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein(11-13), 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.