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In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit.

在发育中的大脑内，神经元集群会组装为功能环路，以调控多样的行为。其中一类进化保守的行为为听觉惊跳反应（acoustic startle response），在斑马鱼中该反应由特征明确的后脑环路介导。尽管目前已鉴定出诸多引导神经元与其突触伴侣定向连接的分子通路，但听觉惊跳环路中不同神经元群体是否、以及在多大程度上共享分子通路以保障协调发育，仍不明确。本研究证实，与平面细胞极性（planar cell polarity, PCP）相关的非经典钙粘蛋白Celsr3、Celsr2，以及Celsr结合蛋白Frizzled 3a（Fzd3a），对两类彼此形成突触连接的神经元的轴突导向至关重要：分别是介导听觉惊跳逃逸反应的命令样神经元Mauthner细胞，以及向Mauthner细胞提供兴奋性输入的螺旋纤维神经元。研究发现，Mauthner轴突向突触靶点的生长对于Mauthner细胞的存活不可或缺。同时我们证实，Mauthner细胞所接收的对称螺旋纤维输入对逃逸方向调控至关重要，而这是应对方向性威胁的必要条件。此外，本研究还明确了Celsr3与Celsr2的不同功能：Celsr3是惊跳环路发育所必需的，而Celsr2并非必需，不过Celsr2可在Mauthner细胞中部分补偿Celsr3缺失带来的缺陷。这与后脑内的面分支运动神经元迁移现象形成对比——后者依赖Celsr2，而我们发现Celsr3对此并非必需。综上，本研究数据揭示了单个PCP组分在听觉惊跳后脑环路组装过程中发挥的关键且独特的作用。