Dync1li1 is required for the survival of mammalian cochlear hair cells by regulating the transportation of autophagosomes

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 fou...

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Bibliographic Details
Published in:PLoS genetics 2022-06, Vol.18 (6), p.e1010232-e1010232
Main Authors: Zhang, Yuan, Zhang, Shasha, Zhou, Han, Ma, Xiangyu, Wu, Leilei, Tian, Mengyao, Li, Siyu, Qian, Xiaoyun, Gao, Xia, Chai, Renjie
Format: Article
Language:English
Subjects:
Apoptosis
Autophagy
Biology and Life Sciences
Cell death
Cochlea
Dynein
Golgi apparatus
Hair cells
Hearing loss
Laboratory animals
Lysosomes
Medicine and Health Sciences
Neonates
Phagosomes
Proteins
Research and Analysis Methods
Retrograde transport
Roles
Vacuoles
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1010232