Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein
Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein
复制标题
Dlic1 缺陷通过破坏动力蛋白的稳定性来损害光感受器的纤毛发生
DOI：
10.1038/cr.2013.59
复制
发表时间：
2013-06-01
期刊：
影响因子：
44.1
通讯作者：
Tao, Wufan
中科院分区：
文献类型：
--
作者：
Kong, Shanshan;Du, Xinrong;Tao, Wufan
胞质动力蛋白1对于真核细胞内沿沿着运输各种必需货物至关重要。然而，在哺乳动物中，很少有突变体可用于研究整个生物体中动力蛋白控制过程中缺陷的影响。在这里，我们删除了小鼠Dlic 1基因编码DLIC 1，动力蛋白复合物的亚基。Dlic 1 −/−小鼠存活，但表现出严重的感光细胞变性。Dlic 1的消融导致外节（OS）蛋白的异位积累，并通过干扰Rab 11-囊泡运输和阻断有效的OS蛋白从高尔基体运输到基体来损害OS生长和光感受器的纤毛发生。我们的研究表明，Dlic 1缺陷部分阻断囊泡出口内质网（ER），但似乎不影响囊泡运输从ER到高尔基体。进一步的机制研究表明，缺乏Dlic 1不稳定的动力蛋白亚基和改变正常的亚细胞分布的动力蛋白在光感受器，可能是由于受损的运输功能的动力蛋白。我们的研究结果表明，Dlic 1在纤毛发生和蛋白质转运到OS中起着重要作用，并且是感光细胞发育和存活所必需的。Dlic 1 −/−小鼠也为研究人类视网膜变性提供了一种新的小鼠模型。
Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells. However, in mammals, few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism. Here, we deleted mouse Dlic1 gene encoding DLIC1, a subunit of the dynein complex. Dlic1−/− mice are viable, but display severe photoreceptor degeneration. Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins, and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rab11-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body. Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER), but seems not to affect vesicle transport from the ER to Golgi. Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors, probably due to the impaired transport function of dynein. Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS, and is required for photoreceptor development and survival. The Dlic1−/− mice also provide a new mouse model to study human retinal degeneration.