Disruption of the autism-related gene Pak1 causes stereocilia disorganization,hair cell loss,and deafness in mice  

作　　者：Cheng Cheng Yilin Hou Zhonghong Zhang Yanfei Wang Ling Lu Liyan Zhang Pei Jiang Song Gao Qiaojun Fang Chengwen Zhu Junyan Gao Xufeng Liu Wei Xie Zhengping Jia Zhigang Xu Xia Gao Renjie Chai 

机构地区：[1]Department of Otolaryngology Head and Neck Surgery,Affiliated Drum Tower Hospital of Nanjing University Medical School,Jiangsu Provincial Key Medical Discipline(Laboratory),Nanjing,Jiangsu 210008,China [2]Research Institute of Otolaryngology,Nanjing,Jiangsu 210008,China [3]State Key Laboratory of Bioelectronics,School of Life Sciences and Technology,Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research,Southeast University,Nanjing,Jiangsu 210096,China [4]Department of Military Psychology,Fourth Military Medical University,Xi'an,Shanxi 710032,China [5]Department of Ophthalmology,Zhongda Hospital Southeast University,Nanjing,Jiangsu 210009,China [6]Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology,Shandong University School of Life Sciences,Qingdao,Shandong 266237,China [7]Jiangsu Rehabilitation Research Center for Hearing and Speech Impairment,Nanjing,Jiangsu 210004,China [8]Neurosciences&Mental Health,The Hospital for Sick Children,Toronto,Ontario M5G 1X8,Canada [9]Department of Physiology,Faculty of Medicine,University of Toronto,Toronto,Ontario M5S 2E8,Canada [10]Co-Innovation Center of Neuroregeneration,Nantong University,Nantong,Jiangsu 226019,China [11]Institute for Stem Cell and Regeneration,Chinese Academy of Science,Beijing 100864,China [12]Beijing Key Laboratory of Neural Regeneration and Repair,Capital Medical University,Beijing 100069,China

出　　处：《Journal of Genetics and Genomics》2021年第4期324-332,共9页遗传学报（英文版）

基　　金：supported by grants from Strategic Priority Research Program of the Chinese Academy of Science(XDA16010303);the National Natural Science Foundation of China(81570921,82030029,81970882,81970884,81900941,81771019,81700913);Natural Science Foundation of Jiangsu Province(BE2019711,BK20190121);the China Postdoctoral Science Foundation(2020M681555);Shenzhen Fundamental Research Program(JCYJ20190814093401920)。

摘　　要：Several clinical studies have reported that hearing loss is correlated with autism in children.However,little is known about the underlying mechanism between hearing loss and autism.p21-activated kinases(PAKs)are a family of serine/threonine kinases that can be activated by multiple signaling molecules,particularly the Rho family of small GTPases.Previous studies have shown that Pak1 mutations are associated with autism.In the present study,we take advantage of Pak1 knockout(Pak1a/a)mice to investigate the role of PAK1 in hearing function.We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell(HC)apoptosis and severe hearing loss.Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of b II-spectrin,which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1à/àmice.Overall,our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function.As the first candidate gene linking autism and hearing loss,Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.

关 键 词：PAK1 Hearing loss Synapse Hair bundle ERM 

分 类 号：R749.94[医药卫生—神经病学与精神病学]