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 negative regulation of SYS-1/β-catenin localization, but MIG-5 has a stronger effect on polarity of SYS-1 localization. We show that MIG-5 controls cortical APR-1/APC localization. DSH-2 and MIG-5 both regulate the localization of WRM-1/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 Dishevelleds as positive regulators of SYS-1/β-catenin. 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 polarity of β-catenin regulation.