Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes.
Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes.
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DOI：
10.1371/journal.pgen.1010232
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发表时间：
2022-06
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
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Dync1li1是细胞质动力蛋白1的一个亚基，在许多组织的细胞内逆行转运中发挥重要作用。然而，Dync1li1在哺乳动物耳蜗中的作用仍然没有调查。我们首先研究了Dync1li1在小鼠耳蜗中的表达模式，发现Dync1li1在新生和成年小鼠耳蜗的毛细胞（HCs）中高度表达。接下来，我们使用Dync1li1敲除（KO）小鼠来研究其对听力的影响，发现Dync1li1的缺失导致通过细胞凋亡的进行性HC损失的早期发作和随后的听力损失。进一步的研究表明，Dync1li1的缺失使动力蛋白不稳定，并改变了动力蛋白的正常功能。此外，Dync1li1 KO导致更薄的高尔基体和LC 3+自噬空泡的积累，从而触发HC凋亡。我们还在OC 1细胞中敲低Dync1li1，发现自噬体的数量显著增加，而自溶酶体的数量减少，这表明Dync1li1敲低导致自噬体向溶酶体的运输受损，因此自噬体的积累导致HC凋亡。我们的研究结果表明，Dync1li1通过调节自噬体运输在HC存活中起着重要作用。听力损失是全球最常见的感觉障碍之一。听力损失的主要原因是耳蜗毛细胞的不可逆损失或功能障碍。识别新的听力损失相关基因并研究其在HC生存中的作用和机制对于预防和治疗遗传性听力损失具有重要意义。细胞质动力蛋白1在小鼠光感受器的纤毛发生和蛋白质转运中起重要作用。在这里，我们描述了Dyncili1（细胞质动力蛋白1的亚基）在小鼠耳蜗中的表达模式，并使用敲除小鼠来研究其在耳蜗毛细胞中的特定作用。
Dync1li1, a subunit of cytoplasmic dynein 1, is reported to play important roles in intracellular retrograde transport in many tissues. However, the roles of Dync1li1 in the mammalian cochlea remain uninvestigated. Here we first studied the expression pattern of Dync1li1 in the mouse cochlea and found that Dync1li1 is highly expressed in hair cells (HCs) in both neonatal and adult mice cochlea. Next, we used Dync1li1 knockout (KO) mice to investigate its effects on hearing and found that deletion of Dync1li1 leads to early onset of progressive HC loss via apoptosis and to subsequent hearing loss. Further studies revealed that loss of Dync1li1 destabilizes dynein and alters the normal function of dynein. In addition, Dync1li1 KO results in a thinner Golgi apparatus and the accumulation of LC3+ autophagic vacuoles, which triggers HC apoptosis. We also knocked down Dync1li1 in the OC1 cells and found that the number of autophagosomes were significantly increased while the number of autolysosomes were decreased, which suggested that Dync1li1 knockdown leads to impaired transportation of autophagosomes to lysosomes and therefore the accumulation of autophagosomes results in HC apoptosis. Our findings demonstrate that Dync1li1 plays important roles in HC survival through the regulation of autophagosome transportation. Hearing loss is one of the most common sensorial disorders globally. The main reason of hearing loss is the irreversible loss or malfunction of cochlear hair cells. Identifying new hearing loss-related genes and investigating their roles and mechanisms in HC survival are important for the prevention and treatment of hereditary hearing loss. Cytoplasmic dynein 1 is reported to play important roles in in ciliogenesis and protein transport in the mouse photoreceptors. Here, we described the expression pattern of Dyncili1 (a subunit of cytoplasmic dynein 1) in the mouse cochlea and used knockout mice to investigate its specific role in the hair cell of cochlea.
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发表时间：
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期刊：
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