Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Department of Molecular Cell Biology, University of California, Berkeley, CA 94720-3204, USA.
Development. 2018 Dec 17;145(24):dev168666. doi: 10.1242/dev.168666.
Signaling that instructs the migration of neurons needs to be tightly regulated to ensure precise positioning of neurons and subsequent wiring of the neuronal circuits. Wnt-Frizzled signaling controls neuronal migration in metazoans, in addition to many other aspects of neural development. We show that VANG-1, a membrane protein that acts in the planar cell polarity (PCP) pathway, antagonizes Wnt signaling by facilitating endocytosis of the Frizzled receptors. Mutations of suppress migration defects of multiple classes of neurons in the Frizzled mutants, and overexpression of causes neuronal migration defects similar to those of the Frizzled mutants. Our genetic experiments suggest that VANG-1 facilitates Frizzled endocytosis through β-arrestin2. Co-immunoprecipitation experiments indicate that Frizzled proteins and VANG-1 form a complex, and this physical interaction requires the Frizzled cysteine-rich domain. Our work reveals a novel mechanism mediated by the PCP protein VANG-1 that downregulates Wnt signaling through Frizzled endocytosis.
信号转导指导神经元的迁移需要被严格调控，以确保神经元的精确定位和随后的神经元回路的连接。Wnt-Frizzled 信号转导除了调控许多其他的神经发育过程外，还控制着后生动物的神经元迁移。我们发现，作为平面细胞极性（PCP）途径中的一个膜蛋白，VANG-1 通过促进 Frizzled 受体的内吞作用来拮抗 Wnt 信号转导。抑制 VANG-1 的突变可以抑制 Frizzled 突变体中多种神经元的迁移缺陷，而过表达 VANG-1 则会导致类似于 Frizzled 突变体的神经元迁移缺陷。我们的遗传实验表明，VANG-1 通过β-arrestin2 促进 Frizzled 内吞。免疫共沉淀实验表明，Frizzled 蛋白和 VANG-1 形成复合物，这种物理相互作用需要 Frizzled 富含半胱氨酸的结构域。我们的工作揭示了一种由 PCP 蛋白 VANG-1 介导的新机制，该机制通过 Frizzled 内吞作用下调 Wnt 信号转导。
