Dync1li1 Is Required For The Survival Of Mammalian Cochlear Hair Cells

Sensorineural hearing loss(HL)is the most common type of HL(accounting for approximately70%).Auditory hair cell(HC)loss or damage is the main reason of sensorineural HL.Many studies reported that several genes are related to HC loss,but there is still a lack of effective preventive and therapeutic treatment.Therefore,discovering new deafness-related genes and studying their mechanisms will provide a theoretical basis for clinical treatment of HL.Dync1li1 is an important binding subunit of cytoplasmic dynein 1 which is responsible for intracellular retrograde transportation and plays important roles in cellular structures and functions in many tissues,including cilium formation in eyes.However,the roles of Dync1li1 in mammalian inner ear remains uninvestigated.Here we investigated the expression pattern and roles of Dync1li1 in the cochlea of mice.First,we studied the expression pattern of Dync1li1 in wild-type mice cochlea of different age after birth and found that Dync1li1 is highly expressed in cochlear HCs of both neonatal and adult mice.Next,we used Dync1li1 knockout(KO)mice to investigate its effects on hearing function.The results showed that deletion of Dync1li1 leads to early onset of progressive HC loss and hearing loss due to HC apoptosis.Further studies revealed that loss of Dync1li1 destabilizes dynein complex,and thus alters the normal subcellular functions of dynein in HCs.In addition,Dync1li1 KO results in thinner lamella Golgi apparatus and accumulation of autophagosomes in HCs,and subsequently results in HC apoptosis.We knocked down(KD)Dync1li1 in OC1 cell line and found that the number of LC3 puncta was significantly increased with co-labeling with the adaptor Rab7,which suggested that Dync1li1 KD led to impaired transportation of autophagosomes to lysosomes.Therefore,the autophagosomes are accumulated in HCs,which resulted in HC apoptosis and hearing loss.All our findings demonstrated that Dync1li1 plays important roles in mammalian HC survival through the regulation of autophagosome transportation.