Spatial control of neurite branching is crucial for the establishment of precise connectivity of the nervous system. However, how extracellular signals specify axon branching sites remains incompletely understood. Here we examine the role of secreted Wnt glycoproteins in specifying neurite branching pattern in the bilaterally symmetric PLM touch neurons. The PLM has an anterior neurite that generates a single synaptic branch at a fairly invariable location. The outgrowth of the PLM branch was preceded by the emergence of a highly localized F-actin patch. In mutants that lost activity for cwn-1/Wnt, egl-20/Wnt, mig-1/Frizzled and vang-1/Strabismus/Vangl2, PLM branches developed at more proximal locations. In these mutants, we observed stronger and more dispersed F-actin signals before the onset of branch outgrowth, suggesting that Wnt-Frizzled/PCP (planar cell polarity) signaling restricted F-actin activity to the distal neurite. While egl-20 was permissive for PLM branching pattern, cwn-1 acted instructively for PLM branch placement. These Wnts promoted endosomal localization of MIG-1 in the proximal PLM neurite. Interestingly, we found that vang-1 was required for endosomal localization of MIG-1. In the absence of VANG-1, MIG-1 was more retained on the plasma membrane. The importance of endocytosis in mediating Frizzled signaling during branching site control was further supported by: (1) Mutations in rabs-5 and arr-1, two genes required for endosomal trafficking and receptor-mediated endocytosis, respectively, caused proximal branching phenotype and dispersal of F-actin activity; (2) MIG-1 C-terminus controled MIG-1 endocytosis and was required for rescue; and (3) VANG-1 and MIG-1 existed in the same protein complex. These findings provide a genetic framework for spatial control of neurite branching by Wnt-Frizzled/PCP signaling that likely occurs in the endosome to pattern F-actin polymerization. (supported by The Ministry of Science and Technology, Taiwan, 103-2320-B-002-050-MY3).
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