Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Development. 2024 Sep 1;151(17). doi: 10.1242/dev.202788. Epub 2024 Sep 5.
Ciliopathies are characterized by the absence or dysfunction of primary cilia. Despite the fact that cognitive impairments are a common feature of ciliopathies, how cilia dysfunction affects neuronal development has not been characterized in detail. Here, we show that primary cilium-mediated signaling is required cell-autonomously by neurons during neural circuit formation. In particular, a functional primary cilium is crucial during axonal pathfinding for the switch in responsiveness of axons at a choice point or intermediate target. Using different animal models and in vivo, ex vivo and in vitro experiments, we provide evidence for a crucial role of primary cilium-mediated signaling in long-range axon guidance. The primary cilium on the cell body of commissural neurons transduces long-range guidance signals sensed by growth cones navigating an intermediate target. In extension of our finding that Shh is required for the rostral turn of post-crossing commissural axons, we suggest a model implicating the primary cilium in Shh signaling upstream of a transcriptional change of axon guidance receptors, which in turn mediate the repulsive response to floorplate-derived Shh shown by post-crossing commissural axons.
纤毛病的特征是主要纤毛缺失或功能障碍。尽管认知障碍是纤毛病的一个常见特征，但纤毛功能障碍如何影响神经元发育还没有详细描述。在这里，我们表明，在神经回路形成过程中，神经元自主地需要初级纤毛介导的信号转导。特别是，在轴突寻径过程中，功能性初级纤毛对于在选择点或中间靶标处的轴突反应性的转换至关重要。通过使用不同的动物模型和体内、离体和体外实验，我们提供了初级纤毛介导的信号转导在长程轴突导向中的关键作用的证据。位于连合神经元细胞体上的初级纤毛转导生长锥在导航中间靶标时感知到的长程导向信号。在我们发现 Shh 对于交叉后连合轴突的头向转弯是必需的这一发现的扩展中，我们提出了一个模型，表明初级纤毛在 Shh 信号转导中位于轴突导向受体的转录变化之前，而轴突导向受体反过来介导交叉后连合轴突对来自基板的 Shh 的排斥反应。
