Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2024 Oct 21;20(10):e1011415. doi: 10.1371/journal.pgen.1011415. eCollection 2024 Oct.
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.
在发育中的大脑中，神经元群组织成功能回路，指导各种行为。其中一种行为是进化上保守的声学惊跳反应，在斑马鱼中由一个定义明确的后脑回路介导。虽然已经确定了许多指导神经元与其突触伙伴连接的分子途径，但尚不清楚惊跳回路中的不同神经元群体是否以及在何种程度上利用共享的分子途径来确保协调的发育。在这里，我们表明，平面细胞极性（PCP）相关的非典型钙粘蛋白 Celsr3 和 Celsr2 以及 Celsr 结合伴侣 Frizzled 3a/Fzd3a，对于与彼此形成突触的两种神经元类型的轴突导向至关重要：发出命令样神经元 Mauthner 细胞，驱动声学惊跳逃避反应，和螺旋纤维神经元向 Mauthner 细胞提供兴奋性输入。我们发现，Mauthner 轴突向突触靶标的生长对于 Mauthner 的存活至关重要。我们还证明，Mauthner 细胞对称的螺旋纤维输入对于逃避方向至关重要，这对于应对定向威胁是必要的。此外，我们确定了 Celsr3 和 Celsr2 的不同作用，因为 Celsr3 对于惊跳回路的发育是必需的，而 Celsr2 是可有可无的，尽管 Celsr2 可以部分补偿 Mauthner 细胞中 Celsr3 的缺失。这与后脑面部分支运动神经元迁移形成对比，后者需要 Celsr2，而我们发现 Celsr3 是可有可无的。总之，我们的数据揭示了个体 PCP 成分在声学惊跳后脑回路组装过程中的关键和独特作用。
