Primary cilia emanate from most human cell types, including neurons. Cilia are important for communicating with the cell’s immediate environment: signal reception and transduction to/from the ciliated cell. Deregulation of ciliary signaling can lead to ciliopathies and certain neurodevelopmental disorders. In the developing brain cilia play well-documented roles for the expansion of the neural progenitor cell pool, while information about the roles of cilia during post-mitotic neuron differentiation and maturation is scarce. We employed ciliated Lund Human Mesencephalic (LUHMES) cells in time course experiments to assess the impact of ciliary signaling on neuron differentiation. By comparing ciliated and non-ciliated neuronal precursor cells and neurons in wild type and in RFX2 -/- mutant neurons with altered cilia, we discovered an early-differentiation “ciliary time window” during which transient cilia promote axon outgrowth, branching and arborization. Experiments in neurons with IFT88 and IFT172 ciliary gene knockdowns, leading to shorter cilia, confirm these results. Cilia promote neuron differentiation by tipping WNT signaling toward the non-canonical pathway, in turn activating WNT pathway output genes implicated in cyto-architectural changes. We provide a mechanistic entry point into when and how ciliary signaling coordinates, promotes and translates into anatomical changes. We hypothesize that ciliary alterations causing neuron differentiation defects may result in “mild” impairments of brain development, possibly underpinning certain aspects of neurodevelopmental disorders.

中文翻译：

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初级纤毛通过WNT信号通路促进人类神经元的分化

初级纤毛源自大多数人类细胞类型，包括神经元。纤毛对于与细胞的直接环境进行通信非常重要：信号接收和传入/传出纤毛细胞的信号传导。纤毛信号传导失调可导致纤毛病和某些神经发育障碍。在发育中的大脑中，纤毛在神经祖细胞池的扩张中发挥着广泛的作用，而有关纤毛在有丝分裂后神经元分化和成熟过程中的作用的信息却很少。我们在时间过程实验中使用纤毛隆德人中脑 (LUHMES) 细胞来评估纤毛信号传导对神经元分化的影响。通过比较野生型和具有改变纤毛的RFX2-/-突变神经元中的纤毛和非纤毛神经元前体细胞和神经元，我们发现了一个早期分化的“纤毛时间窗口”，在此期间短暂的纤毛促进轴突生长、分支和分枝。在 IFT88 和 IFT172 纤毛基因敲低的神经元中进行的实验证实了这些结果，从而导致纤毛变短。纤毛通过将 WNT 信号传导向非规范途径，从而激活与细胞结构变化有关的 WNT 途径输出基因，从而促进神经元分化。我们提供了一个机械切入点，了解纤毛信号何时以及如何协调、促进和转化为解剖学变化。我们假设导致神经元分化缺陷的纤毛改变可能会导致大脑发育的“轻度”损伤，可能是神经发育障碍某些方面的基础。