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Summary Caenorhabditis elegans embryos rapidly diversify cell fate using a modified Wnt/β-catenin signaling strategy to carry out serial asymmetric cell divisions (ACDs). Wnt-dependent ACDs rely on nuclear asymmetry of the transcriptional coactivator SYS-1/β-catenin between daughter cells to differentially activate Wnt-responsive target genes. Here, we investigate how dynamic localization of SYS-1 to mitotic centrosomes influences SYS-1 inheritance in daughter cells and cell-fate outcomes after ACD. Through yeast two-hybrid screening, we identify the centrosomal protein RSA-2 as a SYS-1 binding partner and show that localization of SYS-1 to mitotic centrosomes is dependent on RSA-2. Uncoupling SYS-1 from the centrosome by RSA-2 depletion increases SYS-1 inheritance after ACD and promotes Wnt-dependent cell fate. Photobleaching experiments reveal that centrosome-bound SYS-1 turns over rapidly. Interestingly, disruption of the proteasome leads to an increased accumulation of SYS-1 at the centrosome but disrupts its dynamic turnover. We conclude that centrosomal targeting of SYS-1 promotes its degradation during asymmetric cell division. We propose a model whereby centrosome-associated SYS-1 degradation couples negative regulation with cell-division timing to facilitate SYS-1 clearance from the mother cell at the time of asymmetric division. Based on our observations of centrosomal SYS-1 dynamics, we discuss the possibility that the centrosome may coordinate various cell-cycle-dependent processes by synchronizing mitosis and protein regulation. [ABSTRACT FROM AUTHOR]

The canonical Wnt/beta-catenin pathway is extensively characterized, broadly conserved, and clinically important. In this review, we describe the C. elegans Wnt/beta-catenin asymmetry pathway and suggest that some of its unusual features may have important implications for the canonical Wnt/beta-catenin pathway.

C. elegans SYS-1 has key functional characteristics of a canonical beta-catenin, but no significant sequence similarity. Here, we report the SYS-1 crystal structure, both on its own and in a complex with POP-1, the C. elegans TCF homolog. The two structures possess signature features of canonical beta-catenin and the beta-catenin/TCF complex that could not be predicted by sequence. Most importantly, SYS-1 bears 12 armadillo repeats and the SYS-1/POP-1 interface is anchored by a conserved salt-bridge, the "charged button." We also modeled structures for three other C. elegans beta-catenins to predict the molecular basis of their distinct binding properties. Finally, we generated a phylogenetic tree, using the region of highest structural similarity between SYS-1 and beta-catenin, and found that SYS-1 clusters robustly within the beta-catenin clade. We conclude that the SYS-1 protein belongs to the beta-catenin family and suggest that additional divergent beta-catenins await discovery.