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Hair Cells: From Molecules to Function

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00362

Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice

 Chengwen Zhu1, 2, 3, 4, Cheng Cheng1, 2, 3, 5,  Yanfei Wang6, 7, Muhammad Waqas1, 2, 8,  Shuang Liu9, Weijie Zhu2, Buwei Shao2,  Zhong Zhang2, Xiaoqian Yan2, Qingqing He3, 4,  Zhengrong Xu3, 4,  Chenjie Yu3, 4, Xiaoyun Qian3, 4, Ling Lu10, Shasha Zhang1, 2, 3, 5, Yuan Zhang2,  Wei Xiong9, Xia Gao3, 4*,  Zhigang Xu6, 7* and  Renjie Chai1, 2, 3, 5*
  • 1Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, southeast university, China
  • 2Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, China
  • 3Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, China
  • 4Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, China
  • 5Co-Innovation Center of Neuroregeneration, Nantong University, China
  • 6School of Life Sciences, Shandong University, China
  • 7Shandong Provincial Collaborative Innovation Center of Cell Biology, Shandong Normal University, China
  • 8Department of Biotechnology, Federal Urdu University of Arts, Sciences and Technology Islamabad, Pakistan
  • 9School of Life Sciences, IDG/McGovern Institute for Brain Research,, Tsinghua University, China
  • 10Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, China

ARHGEF6 belongs to the family of guanine nucleotide exchange factors (GEFs) for Rho GTPases, and it specifically activates Rho GTPases CDC42 and RAC1. Arhgef6 is the X-linked intellectual disability gene also known as XLID46, and clinical features of patients carrying Arhgef6 mutations include intellectual disability and, in some cases, sensorineural hearing loss. Rho GTPases act as molecular switches in many cellular processes. Their activities are regulated by binding or hydrolysis of GTP, which is facilitated by guanine nucleotide exchange factors and GTPase-activating proteins, respectively. RAC1 and CDC42 have been shown to play important roles in hair cell (HC) stereocilia development. However, the role of ARHGEF6 in inner ear development and hearing function has not yet been investigated. Here, we found that ARHGEF6 is expressed in mouse cochlear HCs, including the HC stereocilia. We established Arhgef6 knockdown mice using the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR-Cas9) genome editing technique. We showed that ARHGEF6 was indispensable for the maintenance of outer hair cell (OHC) stereocilia, and loss of ARHGEF6 in mice caused HC stereocilia deficits that eventually led to progressive HC loss and hearing loss. However, the loss of ARHGEF6 did not affect the synapse density and did not affect the mechanoelectrical transduction currents in OHCs at postnatal day 3. At the molecular level, the levels of active CDC42 and RAC1 were dramatically decreased in the Arhgef6 knockdown mice, suggesting that ARHGEF6 regulates stereocilia maintenance through RAC1/CDC42.

Keywords: Arhgef6, Hair cells, Stereocilia, sensorineural hearing loss(SNHL), guanine nucleotide exchange factors(GEF)

Received: 14 Mar 2018; Accepted: 13 Sep 2018.

Edited by:

David He, Creighton University School of Medicine, United States

Reviewed by:

Pierre Billuart, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Allison B. Coffin, Washington State University, United States  

Copyright: © 2018 Zhu, Cheng, Wang, Waqas, Liu, Zhu, Shao, Zhang, Yan, He, Xu, Yu, Qian, Lu, Zhang, Zhang, Xiong, Gao, Xu and Chai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Xia Gao, Nanjing Drum Tower Hospital, Department of Otolaryngology Head and Neck Surgery, Nanjing, 210008, Jiangsu, China,
Prof. Zhigang Xu, Shandong University, School of Life Sciences, Jinan, Shandong, China,
Prof. Renjie Chai, Nanjing Drum Tower Hospital, Department of Otolaryngology Head and Neck Surgery, Nanjing, 210008, Jiangsu, China,