Figure 2. Antagonistic interactions of planar cell polarity components in axon guidance and spatial and temporal regulation by Sonic Hedgehog.

A. Dishevelled1 and 3 induce Frizzled3 hyperphosphorylation and increase the cell surface presence of Frizzled3, reducing the activation of downstream signals such as JNK.

B. Vangl2 and Dishevelled2 can antagonize Dishevelled1 and 3 by inhibiting Frizzled3 phosphorylation. The unphosphorylated Frizzled3 binds to Arf6, which mediates Frizzled3 endocytosis. aPKC is required for Dishevelled2 to inhibit Dishevelled1/3-induced Frizzled3 phosphorylation.

C. Vangl2 protein is enriches on the tips of the filopodia that are extending but not on the tips of filopodia that are shrinking.

D. A hypothesis for how the antagonistic interactions of planar cell polarity signaling components may amplify the shallow Wnt gradient into highly spatially asymmetric and polarized signals inside the growth cone to cause turning.

E. The antagonism between Dishevelled and Vangl in Frizzled phosphorylation and endocytosis and dual functions of Dishevelled are conserved in C. elegans.

F. Spinal cord commissural axons turn anteriorly only after midline crossing even though their growth cones are exposed to the anterior-high-posterior-low Wnt gradient when they reach the floor plate before they cross.

G. Shisa2 binds to Frizzzled3 and retains Frizzzled3 in the endoplasmic reticulum, preventing Frizzled3 from being trafficked to the growth cone surface. Sonic Hedgehog down regulates the expression of Shisa2, allowing Frizzled3 to come to the growth cone surface.

H. Sonic Hedgehog is highly but specifically expressed in the floor plate. When spinal cord commissural axons reach midline, their growth cones detect Sonic Hedgehog, and via smoothened signaling, retrogradely signal to the cell body to down regulate the expression of Shisa2 so that Frizzled3 can move to the cell surface to detect Wnt proteins and their gradient.