Lzts2 Regulates Embryonic Cell Movements and Dorsoventral Patterning through Interaction with and Export of Nuclear β-Catenin in Zebrafish

Abstract

Leucine zipper tumor suppressor 2 (Lzts2) functions in the development and progression of various tumors, but its activities in vertebrate embryogenesis remain unclear. Here, we demonstrate that lzts2 transcripts are of maternal origin in zebrafish embryos. Activation of BMP signaling up-regulates zygotic expression of lzts2, whereas canonical Wnt signaling acts upstream of BMP signaling to inhibit lzts2 expression. Abrogation of lzts2 expression by its specific morpholino-enhanced gastrula convergence and extension (CE) movements, dorsalized early embryos, and inhibited specification of midline progenitors for pancreas, liver, and heart. In contrast, ectopic expression of lzts2 led to the delay of CE movements and midline convergence of organ progenitors and resulted in a certain ratio of ventralized embryos. Mechanistically, Lzts2 regulates the migration of embryonic cells and dorsoventral patterning through its limitation of Wnt/β-catenin activity, because it physically interacts with β-catenin-1 and -2 and transports them out of the nucleus. In addition, both β-catenin-1 and -2 exhibit redundant functions in activation of Stat3 signaling and in induction of Wnt5/11 expression through inhibition of BMP signaling and stimulation of Cyclops and Squint expression. Thus, Lzts2 regulates gastrula CE movements, dorsoventral patterning, and midline convergence and specification of organ precursors through interaction with and the export of nuclear β-catenins in zebrafish.