Role for intraflagellar transport in building a functional transition zone
Role for intraflagellar transport in building a functional transition zone
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DOI：
10.15252/embr.201845862
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发表时间：
2018-12-01
期刊：
影响因子：
7.7
通讯作者：
Leroux, Michel R.
中科院分区：
文献类型：
--
作者：
Jensen, Victor L.;Lambacher, Nils J.;Leroux, Michel R.
由纤毛功能障碍引起的遗传性疾病，称为纤毛病，经常涉及鞭毛内转运（IFT）系统。IFT亚单位的突变-包括IFT-动力蛋白运动DYNC 2 H1-损害纤毛结构和Hedgehog信号传导，通常导致“骨骼”纤毛病变，如青少年窒息性胸部营养不良。有趣的是，IFT基因突变也会导致眼睛、肾脏和大脑的纤毛病变，这些疾病通常与过渡区（TZ）的缺陷有关，TZ是一种与刺猬信号有关的纤毛门。在这里，我们确定一个C。elegans温度敏感（ts）IFT-动力蛋白突变体（che-3;人DYNC 2 H1），并使用它来显示逆行IFT在顺行运输和纤毛维持中的作用。出乎意料的是，正确的TZ组装和纤毛周围蛋白的门控功能也需要IFFT-动力蛋白。使用新的TS-IFT-动力蛋白的可逆性，我们表明，恢复IFT在成人（发育后）逆转睫状结构，TZ蛋白定位和睫状门控缺陷。值得注意的是，这种逆转TZ缺陷的能力随着动物年龄的增长而下降。总之，我们的研究结果揭示了一个以前未知的作用，IFT在TZ组装后生动物，提供了新的见解的病理机制和潜在的表型重叠IFT和TZ-associated ciliopathies。
Synopsis Genetic disorders caused by cilia dysfunction, termed ciliopathies, frequently involve the intraflagellar transport (IFT) system. Mutations in IFT subunits-including IFT-dynein motor DYNC2H1-impair ciliary structures and Hedgehog signalling, typically leading to "skeletal" ciliopathies such as Jeune asphyxiating thoracic dystrophy. Intriguingly, IFT gene mutations also cause eye, kidney and brain ciliopathies often linked to defects in the transition zone (TZ), a ciliary gate implicated in Hedgehog signalling. Here, we identify a C. elegans temperature-sensitive (ts) IFT-dynein mutant (che-3; human DYNC2H1) and use it to show a role for retrograde IFT in anterograde transport and ciliary maintenance. Unexpectedly, correct TZ assembly and gating function for periciliary proteins also require IFT-dynein. Using the reversibility of the novel ts-IFT-dynein, we show that restoring IFT in adults (post-developmentally) reverses defects in ciliary structure, TZ protein localisation and ciliary gating. Notably, this ability to reverse TZ defects declines as animals age. Together, our findings reveal a previously unknown role for IFT in TZ assembly in metazoans, providing new insights into the pathomechanism and potential phenotypic overlap between IFT- and TZ-associated ciliopathies.