Centre de Génétique et de Physiologie Moléculaire et Cellulaire, UMR 5534 CNRS, Université Claude Bernard Lyon 1, Villeurbanne 69622, France.
Hum Mol Genet. 2014 Feb 1;23(3):563-77. doi: 10.1093/hmg/ddt445. Epub 2013 Sep 18.
Cilia are evolutionarily conserved organelles endowed with essential physiological and developmental functions. In humans, disruption of cilia motility or signaling leads to complex pleiotropic genetic disorders called ciliopathies. Cilia motility requires the assembly of multi-subunit motile components such as dynein arms, but mechanisms underlying their assembly pathway and transport into the axoneme are still largely unknown. We identified a previously uncharacterized coiled-coil domain containing protein CCDC151, which is evolutionarily conserved in motile ciliated species and shares ancient features with the outer dynein arm-docking complex 2 of Chlamydomonas. In Drosophila, we show that CG14127/CCDC151 is associated with motile intraflagellar transport (IFT)-dependent cilia and required for geotaxis behavior of adult flies. In zebrafish, Ccdc151 is expressed in tissues with motile cilia, and morpholino-induced depletion of Ccdc151 leads to left-right asymmetry defects and kidney cysts. We demonstrate that Ccdc151 is required for proper motile function of cilia in the Kupffer's vesicle and in the pronephros by controlling dynein arm assembly, showing that Ccdc151 is a novel player in the control of IFT-dependent dynein arm assembly in animals. However, we observed that CCDC151 is also implicated in other cellular functions in vertebrates. In zebrafish, ccdc151 is involved in proper orientation of cell divisions in the pronephros and genetically interacts with prickle1 in this process. Furthermore, knockdown experiments in mammalian cells demonstrate that CCDC151 is implicated in the regulation of primary cilium length. Hence, CCDC151 is required for motile cilia function in animals but has acquired additional non-motile functions in vertebrates.
纤毛是具有重要生理和发育功能的进化保守细胞器。在人类中，纤毛运动或信号的破坏导致称为纤毛病的复杂多效遗传疾病。纤毛运动需要多亚基运动组件的组装，例如动力蛋白臂，但它们的组装途径和向轴丝的运输的机制在很大程度上仍然未知。我们鉴定了一种以前未被表征的卷曲螺旋结构域包含蛋白 CCDC151，它在运动纤毛物种中是进化保守的，并且与衣藻的外动力蛋白臂对接复合物 2 具有古老的特征。在果蝇中，我们表明 CG14127/CCDC151 与依赖于运动性内鞭毛运输 (IFT)的纤毛相关，并且是成年果蝇的趋地行为所必需的。在斑马鱼中，Ccdc151 在具有运动纤毛的组织中表达，并且 Ccdc151 的形态发生诱导耗竭导致左右不对称缺陷和肾脏囊肿。我们证明 Ccdc151 通过控制动力蛋白臂组装对于 Kuffer 囊泡和前肾中的纤毛的适当运动功能是必需的，表明 Ccdc151 是控制动物中 IFT 依赖性动力蛋白臂组装的新成员。然而，我们观察到 CCDC151 也参与脊椎动物中的其他细胞功能。在斑马鱼中，ccdc151 参与前肾细胞分裂的正确定向，并且在该过程中与 prickle1 遗传相互作用。此外，哺乳动物细胞中的敲低实验表明 CCDC151 参与初级纤毛长度的调节。因此，CCDC151 是动物中运动性纤毛功能所必需的，但在脊椎动物中获得了额外的非运动性功能。
