Frontiers in Molecular Neuroscience (Oct 2018)
Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice
- Chengwen Zhu,
- Chengwen Zhu,
- Chengwen Zhu,
- Cheng Cheng,
- Cheng Cheng,
- Cheng Cheng,
- Cheng Cheng,
- Yanfei Wang,
- Yanfei Wang,
- Waqas Muhammad,
- Waqas Muhammad,
- Shuang Liu,
- Weijie Zhu,
- Buwei Shao,
- Zhong Zhang,
- Xiaoqian Yan,
- Qingqing He,
- Zhengrong Xu,
- Chenjie Yu,
- Xiaoyun Qian,
- Ling Lu,
- Shasha Zhang,
- Shasha Zhang,
- Shasha Zhang,
- Shasha Zhang,
- Yuan Zhang,
- Wei Xiong,
- Xia Gao,
- Xia Gao,
- Zhigang Xu,
- Zhigang Xu,
- Renjie Chai,
- Renjie Chai,
- Renjie Chai,
- Renjie Chai,
- Renjie Chai
Affiliations
- Chengwen Zhu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Chengwen Zhu
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Chengwen Zhu
- Research Institute of Otolaryngology, Nanjing, China
- Cheng Cheng
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Cheng Cheng
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Cheng Cheng
- Research Institute of Otolaryngology, Nanjing, China
- Cheng Cheng
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Yanfei Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, China
- Yanfei Wang
- Shandong Provincial Collaborative Innovation Center of Cell Biology, Shandong Normal University, Jinan, China
- Waqas Muhammad
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Waqas Muhammad
- Department of Biotechnology, Federal Urdu University of Arts, Science and Technology, Karachi, Pakistan
- Shuang Liu
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China
- Weijie Zhu
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Buwei Shao
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Zhong Zhang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Xiaoqian Yan
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Qingqing He
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Zhengrong Xu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Chenjie Yu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Xiaoyun Qian
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Ling Lu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Shasha Zhang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Shasha Zhang
- Research Institute of Otolaryngology, Nanjing, China
- Shasha Zhang
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Shasha Zhang
- Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
- Yuan Zhang
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Wei Xiong
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China
- Xia Gao
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Xia Gao
- Research Institute of Otolaryngology, Nanjing, China
- Zhigang Xu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, China
- Zhigang Xu
- Shandong Provincial Collaborative Innovation Center of Cell Biology, Shandong Normal University, Jinan, China
- Renjie Chai
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China
- Renjie Chai
- Research Institute of Otolaryngology, Nanjing, China
- Renjie Chai
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Renjie Chai
- Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
- Renjie Chai
- 0Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- DOI
- https://doi.org/10.3389/fnmol.2018.00362
- Journal volume & issue
-
Vol. 11
Abstract
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 GEFs 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
