Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice
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 intel...
| मुख्य लेखकों: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| स्वरूप: | लेख |
| भाषा: | English |
| प्रकाशित: |
Frontiers Media S.A.
2018-10-01
|
| श्रृंखला: | Frontiers in Molecular Neuroscience |
| विषय: | |
| ऑनलाइन पहुंच: | https://www.frontiersin.org/article/10.3389/fnmol.2018.00362/full |
| _version_ | 1828196227810852864 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Chengwen Zhu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:57:59Z |
| format | Article |
| id | doaj.art-d13f9148e5aa4b0fae4afb8a1be4e24f |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-12T09:57:59Z |
| publishDate | 2018-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-d13f9148e5aa4b0fae4afb8a1be4e24f2022-12-22T03:37:38ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-10-011110.3389/fnmol.2018.00362373994Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in MiceChengwen Zhu0Chengwen Zhu1Chengwen Zhu2Cheng Cheng3Cheng Cheng4Cheng Cheng5Cheng Cheng6Yanfei Wang7Yanfei Wang8Waqas Muhammad9Waqas Muhammad10Shuang Liu11Weijie Zhu12Buwei Shao13Zhong Zhang14Xiaoqian Yan15Qingqing He16Zhengrong Xu17Chenjie Yu18Xiaoyun Qian19Ling Lu20Shasha Zhang21Shasha Zhang22Shasha Zhang23Shasha Zhang24Yuan Zhang25Wei Xiong26Xia Gao27Xia Gao28Zhigang Xu29Zhigang Xu30Renjie Chai31Renjie Chai32Renjie Chai33Renjie Chai34Renjie Chai35Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaResearch Institute of Otolaryngology, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaResearch Institute of Otolaryngology, Nanjing, ChinaCo-Innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaShandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, ChinaShandong Provincial Collaborative Innovation Center of Cell Biology, Shandong Normal University, Jinan, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaDepartment of Biotechnology, Federal Urdu University of Arts, Science and Technology, Karachi, PakistanSchool of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaResearch Institute of Otolaryngology, Nanjing, ChinaCo-Innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaJiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaSchool of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, ChinaResearch Institute of Otolaryngology, Nanjing, ChinaShandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, ChinaShandong Provincial Collaborative Innovation Center of Cell Biology, Shandong Normal University, Jinan, ChinaKey Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, ChinaResearch Institute of Otolaryngology, Nanjing, ChinaCo-Innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaJiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China0Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, ChinaARHGEF6 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.https://www.frontiersin.org/article/10.3389/fnmol.2018.00362/fullArhgef6hair cellsstereociliasensorineural hearing lossguanine nucleotide exchange factors |
| spellingShingle | 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 Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice Frontiers in Molecular Neuroscience Arhgef6 hair cells stereocilia sensorineural hearing loss guanine nucleotide exchange factors |
| title | Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice |
| title_full | Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice |
| title_fullStr | Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice |
| title_full_unstemmed | Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice |
| title_short | Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice |
| title_sort | loss of arhgef6 causes hair cell stereocilia deficits and hearing loss in mice |
| topic | Arhgef6 hair cells stereocilia sensorineural hearing loss guanine nucleotide exchange factors |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2018.00362/full |
| work_keys_str_mv | AT chengwenzhu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengwenzhu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengwenzhu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengcheng lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengcheng lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengcheng lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chengcheng lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT yanfeiwang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT yanfeiwang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT waqasmuhammad lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT waqasmuhammad lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT shuangliu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT weijiezhu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT buweishao lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT zhongzhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT xiaoqianyan lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT qingqinghe lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT zhengrongxu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT chenjieyu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT xiaoyunqian lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT linglu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT shashazhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT shashazhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT shashazhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT shashazhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT yuanzhang lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT weixiong lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT xiagao lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT xiagao lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT zhigangxu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT zhigangxu lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT renjiechai lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT renjiechai lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT renjiechai lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT renjiechai lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice AT renjiechai lossofarhgef6causeshaircellstereociliadeficitsandhearinglossinmice |