A Wnt-planar polarity pathway instructs neurite branching by restricting F-actin assembly through endosomal signaling

Spatial arrangement of neurite branching is instructed by both attractive and repulsive cues. Here we show that in C. elegans, the Wnt family of secreted glycoproteins specify neurite branching sites in the PLM mechanosensory neurons. Wnts function through MIG-1/Frizzled and the planar cell polarity protein (PCP) VANG-1/Strabismus/Vangl2 to restrict the formation of F-actin patches, which mark branching sites in nascent neurites. We find that VANG-1 promotes Wnt signaling by facilitating Frizzled endocytosis and genetically acts in a common pathway with arr-1/β-arrestin, whose mutation results in defective PLM branching and F-actin patterns similar to those in the Wnt, mig-1 or vang-1 mutants. On the other hand, the UNC-6/Netrin pathway intersects orthogonally with Wnt-PCP signaling to guide PLM branch growth along the dorsal-ventral axis. Our study provides insights for how attractive and repulsive signals coordinate to sculpt neurite branching patterns, which are critical for circuit connectivity.神经突分支的空间排布受吸引性与排斥性导向线索共同调控。本研究表明，在秀丽隐杆线虫（C. elegans）中，分泌型糖蛋白Wnt家族可指定PLM机械感受神经元的神经突分支位点。Wnt信号通过MIG-1/卷曲蛋白（Frizzled）以及平面细胞极性蛋白（PCP）VANG-1/Strabismus/Vangl2发挥功能，以限制丝状肌动蛋白斑的形成——该斑是新生神经突分支位点的标志性结构。我们发现，VANG-1通过促进卷曲蛋白的内吞作用增强Wnt信号通路，并在遗传上与arr-1/β抑制蛋白（β-arrestin）处于同一共同通路；arr-1的突变会导致PLM分支缺陷与丝状肌动蛋白模式异常，其表型与Wnt、mig-1或vang-1突变体相似。另一方面，UNC-6/轴突导向蛋白（Netrin）通路可与Wnt-PCP信号通路正交交互，引导PLM分支沿背腹轴生长。本研究为吸引性与排斥性信号如何协同塑造神经突分支模式（该模式对神经环路连接至关重要）提供了新的理论见解。