Zebrafish Nkd1 promotes Dvl degradation and is required for left-right patterning

The establishment of the left-right (LR) axis in zebrafish embryos relies on signals from the dorsal forerunner cells (DFC) and the Kupffer's vesicle (KV). While the Wnt signaling network influences many aspects of embryonic development, its precise role in LR patterning is still unclear. One branch of the Wnt network leads to stabilization of β-catenin and activation of downstream target genes. Other Wnt ligands appear to act independently of β-catenin to modulate calcium release and influence cell polarity. Central to regulation of β-catenin and coordination of convergent extension (CE) movements is Dishevelled (Dvl). Naked Cuticle (Nkd) binds Dvl and modulates β-catenin-dependent and independent Wnt signaling. Here, we analyze the expression patterns of three zebrafish Nkd homologs and find enriched expression of nkd1 in DFCs and KV. Dvl is degraded upon Nkd1 overexpression in zebrafish. Knockdown of Nkd1 specifically in the DFC results in β-catenin nuclear localization and transcriptional activation as well as alterations to DFC migration, KV formation, ciliogenesis and LR patterning. Furthermore, we identify asymmetric expression of the Nodal antagonist charon around the KV and show that Nkd1 knockdown impacts asymmetric charon expression. Our findings show that Nkd1 acts as a β-catenin antagonist in the DFCs necessary for LR patterning.