Dock4 is required for the maintenance of cochlear hair cells and hearing function  

作　　者：Guodong Hong Xiaolong Fu Jieyu Qi Buwei Shao Xuan Han Yuan Fang Shuang Liu Cheng Cheng Chengwen Zhu Junyan Gao Xia Gao Jie Chen Ming Xia Wei Xiong Renjie Chai 

机构地区：[1]State Key Laboratory of Digital Medical Engineering,Department of Otolaryngology Head and Neck Surgery,Zhongda Hospital,School of Life Sciences and Technology,Advanced Institute for Life and Health,Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research,Southeast University,Nanjing 210096,China [2]School of Life Sciences,IDG/McGovern Institute for Brain Research,Tsinghua University,Beijing 100083,China [3]Department of Otolaryngology Head and Neck Surgery,Jiangsu Provincial Key Medical Discipline(Laboratory),Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing 210008,China [4]Research Institute of Otolaryngology,Nanjing 210008,China [5]Jiangsu Rehabilitation Research Center for Hearing and Speech Impairment,Nanjing,Jiangsu 210004,China [6]Department of Otolaryngology,Shandong Provincial Hospital Affiliated to Shandong First Medical University,Shandong 250000,China [7]Medical Science and Technology Innovation Center,Shandong First Medical University&Shandong Academy of Medical Sciences,Shandong 250022,China [8]Co-Innovation Center of Neuroregeneration,Nantong University,Nantong 226001,China [9]Institute for Stem Cell and Regeneration,Chinese Academy of Science,Beijing 100101,China [10]Beijing Key Laboratory of Neural Regeneration and Repair,Capital Medical University,Beijing 100069,China [11]Department of Otolaryngology Head and Neck Surgery,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 610072

出　　处：《Fundamental Research》2023年第4期557-569,共13页自然科学基础研究（英文版）

基　　金：This work was supported by grants from National Key R&D Program of China(2021YFA1101300,2020YFA0112503,2020YFA0113600);the Strategic Priority Research Program of the Chinese Academy of Science(XDA16010303);the National Natural Science Foundation of China(82030029,81970882,82071013,81870721,92149304,82000984);the Natural Science Foundation of Jiangsu Province(BE2019711);the Science and Technology Department of Sichuan Province(2021YFS0371);the Shenzhen Fundamental Research Program(JCYJ20190814093401920,JCYJ20210324125608022);the China National Postdoctoral Program for Innovative Talents(BX20200082);the Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(SKLGE-2109).

摘　　要：Auditory hair cells(HCs)are the mechanosensory receptors of the cochlea,and HC loss or malfunction can result from genetic defects.Dock4,a member of the Dock180-related protein superfamily,is a guanine nucleotide exchange factor for Rac1,and previous reports have shown that Dock4 mutations are associated with autism spectrum disorder,myelodysplastic syndromes,and tumorigenesis.Here,we found that Dock4 is highly expressed in the cochlear HCs of mice.However,the role of Dock4 in the inner ear has not yet been investigated.Taking advantage of the piggyBac transposon system,Dock4 knockdown(KD)mice were established to explore the role of Dock4 in the cochlea.Compared to wild-type controls,Dock4 KD mice showed significant hearing impairment from postnatal day 60.Dock4 KD mice showed hair bundle deficits and increased oxidative stress,which eventually led to HC apoptosis,late-onset HC loss,and progressive hearing loss.Furthermore,molecular mechanism studies showed that Rac1/β-catenin signaling was significantly downregulated in Dock4 KD cochleae and that this was the cause for the disorganized stereocilia and increased oxidative stress in HCs.Overall,our work demonstrates that the Dock4/Rac1/β-catenin signaling pathway plays a critical role in the maintenance of auditory HCs and hearing function.

关 键 词：Hair cell STEREOCILIA Oxidative stress APOPTOSIS Hearing loss Dock4 

分 类 号：R764[医药卫生—耳鼻咽喉科]