| Project/Area Number |
15K15625
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
KIKKAWA Yoshiaki 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, プロジェクトリーダー (20280787)
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| Co-Investigator(Renkei-kenkyūsha) |
SEKI Yuta 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (20280787)
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| Research Collaborator |
SHITARA Hiroshi 公益財団法人東京都医学総合研究所, 基盤技術開発センター, 主任基盤技術研究職員
YASUDA Syumpei 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 主任研究員
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 遺伝学 / 耳科学 / Myosin VI / 有毛細胞 / 難聴 / 選択的スプライシング / ゲノム編集 / トランスジェニックマウス / ミオシンVI |
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| Outline of Final Research Achievements |
Mutations in myosin VI gene (MYO6) contribute to hearing loss in humans. Myo6 null mutant mice exhibit congenital defects in balance and hearing caused by the fusion of stereocilia of inner ear hair cells. We identified a splicing isoform with an alternatively spliced 9-bp micro-exon, and confirmed that this isoform is transcribed and highly expressed in the inner ear. To explore the function of this isoform, we established model mice in which the alternative splicing of the micro-exon was blocked, using CRISPR/Cas9-mediated genome editing. The behavior of the isoform-specific null mutants was normal; however, the mutants developed severe hearing loss at one month of age and exhibited stereociliary degeneration and severe loss of outer hair cells. The phenotypes of the isoform-specific null mutants differed from those of Myo6 null mutants. Thus, our results suggest that different isoforms have distinct roles in the development and/or maintenance of outer hair cells.
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