The canonical Wnt signaling is one of main pathways for intracellular signal transduction. The activation of this pathway results in nuclear accumulation of beta-catenin, which in turn interacts with transcriptional factors such as TCF to initiate the transcriptional expression of downstream genes that are essential for the proliferation, differentiation, apoptosis and migration of cells. Therefore, activity of this pathway is crucial for early embryonic development and formation of vertebrate organs and its abnormal activation is closely associated with the development and progression of various human diseases. Currently, further investigations are needed to understand the roles of canonical Wnt signaling in the formation of vertebrate organs, and the molecular mechanisms controlling the intracellular signaling of this pathway.  

A research group led by Prof. CUI Zongbin at the Institute of Hydrobiology, Chinese Academy of Sciences (IHB), has demonstrated the control of canonical Wnt signalingactivity by the caveolin-1 and b-catenin interaction (2010, Developmental Biology, 344: 211-223). Recently, this group further investigated the spatiotemporal expression, transcriptional regulation and molecular mechanisms underlying developmental functions of Lzts2 in zebrafish. They demonstrate that Lzts2 is involved in the control of gastrula convergence and extension (C&E) movements, dorsoventral patterning of early embryos, and convergence and specification of midline progenitors for pancreas, liver and heart.  

Mechanistically, Lzts2 regulates the migration of embryonic cells and dorsoventral patterning through its limitation of Wnt/β-catenin activity, since it physically interacts with β-catenin-1 and -2 and transports them out of the nucleus in zebrafish. Based on findings from this and previous studies, they have proposed a model for the limitation of C&E movements by Lzts2.In this model, Lzts2 negatively regulates activities of canonical Wnt signaling through the export of nuclear β-catenin-1 and -2. Both β-catenin-1 and -2 are able to inhibit the activity of Bmp signaling and stimulate the activity of Stat3 and expression of Cyclops and Squint. Squint and Cyclops stimulate expression of Wnt5 and Wnt11, while Bmps inhibits their expression. Thus, Lzts2 negatively regulates gastrula C&E movements through inhibition of non-canonical Wnt and Stat3 signaling in zebrafish. In addition, a regulatory loop appears to tightly control the expression of Lzts2 gene by Wnt/β-catenin and Bmp signaling.  

Moreover, they have determined the amino acid sequences in Lzts2 that are necessary for its interaction with b-catenin by using mutagenesis analysis. These findings have provided clues for further understanding of Wnt signaling regulation, developmental functions and molecular mechanisms in human diseases, and for the design of small molecular drugs targeting motifs of Lzts2.  

The results were published online in the Journal Biological Chemistry （http://www.jbc.org/cgi/doi/10.1074/jbc.M111.267328）on November 4, 2011.