Wnt proteins act as guidance cues that either repel or attract navigating axons along the A-P axis. The intracellular mechanisms that mediate and fine-tune the activity of Wnt signaling in axon guidance, however, remain poorly understood. Previous studies in C. elegans (Hilliard and Bargmann 2006) suggested that mutations in
lin-44/Wnt and
lin-17/Fzd induce the reversal of neurite orientation in the PLM neurons. Wild type PLMs grow a long anteriorly directed process and a short but prominent posteriorly directed one, whereas PLMs in
lin-44 and
lin-17 mutants display a short anterior process and a long posterior process that often turns around at the tip of the tail and continues to grow anteriorly, and this phenotype was interpreted as a defect in cellular polarity. Recent experiments in our lab, however, suggest that Wnts act as repellents that regulate PLM neurite outgrowth. First,
lin-44 is normally expressed posterior to the PLM cell body and caused the shortening of the PLM posterior process when overexpressed from its own promoter. Second, misexpression of
lin-44 anterior to the PLM cell body elongated the PLM posterior process. These observations can only be explained by a repelling activity of Wnts. Furthermore, we found that two Dishevelled (Dvl) proteins, DSH-1 and MIG-5, act redundantly downstream of the LIN-17/Fzd receptor; specifically
dsh-1 mig-5 double but not single mutants phenocopied
lin-17 and
lin-44 animals. Mutations in none of the Wnt signaling components downstream of Dvl phenocopied
lin-17 mutants, suggesting extensive genetic redundancy. Nonetheless, we found that mutations in
bar-1/ beta-catenin and
jnk-1/JNK caused an elongation of the PLM posterior process, indicating that components from both the canonical beta-catenin pathway and the PCP pathway mediate the repelling activity of Wnts. Surprisingly,
dsh-1 single mutants had significantly shortened PLM posterior process, a phenotype opposite to that of
lin-17 mutants. Based on studies in frogs and mice, we hypothesized that DSH-1 attenuates the repelling activity of Wnts by inducing phosphorylation of the cytoplasmic tail of LIN-17, thereby enabling the growth of a posteriorly directed neurite. Further studies showed that the DEP domain of DSH-1 is essential for this attenuation and that five putative PKC phosphorylation sites in the LIN-17 C-terminal intracellular region are important for DSH-1-mediated down-regulation. We also found that the PCP pathway components VANG-1/Van Gogh and PRKL-1/Prickle antagonized the function of DSH-1 in attenuating Wnt signaling. Overall, our results suggest that negative feedback by DSH-1 attenuates the repelling activity of Wnts, thus allowing the growth of the PLM posteriorly-directed neurite.