Unique and redundant β-catenin regulatory roles of two Dishevelled paralogs during C. elegans asymmetric cell division.

The Wnt/β-catenin signaling pathway is utilized across metazoans. However, the mechanism of signal transduction, especially dissociation of the β-catenin destruction complex by Dishevelled proteins, remains controversial. Here, we describe the function of the Dishevelled paralogs DSH-2 and MIG-5 in the Wnt/β-catenin asymmetry (WβA) pathway in Caenorhabditis elegans, where WβA drives asymmetric cell divisions throughout development. We find that DSH-2 and MIG-5 redundantly regulate cell fate in hypodermal seam cells. Similarly, both DSH-2 and MIG-5 are required for positive regulation of SYS-1 (a C. elegans β-catenin), but MIG-5 has a stronger effect on the polarity of SYS-1 localization. We show that MIG-5 controls cortical APR-1 (the C. elegans APC) localization. DSH-2 and MIG-5 both regulate the localization of WRM-1 (another C. elegans β-catenin), acting together as negative regulators of WRM-1 nuclear localization. Finally, we demonstrate that overexpression of DSH-2 or MIG-5 in seam cells leads to stabilization of SYS-1 in the anterior seam daughter, solidifying the Dishevelled proteins as positive regulators of SYS-1. Overall, we have further defined the role of Dishevelled in the WβA signaling pathway, and demonstrated that DSH-2 and MIG-5 regulate cell fate, β-catenin nuclear levels and the polarity of β-catenin regulation.