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Affiliation |
Faculty of Medicine School of Medicine Department of Medical Sciences, Pharmacology |
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TAKEYA Ryu
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Research Areas 【 display / non-display 】
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Life Science / Pharmacology
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Life Science / Pathological biochemistry
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Life Science / Medical biochemistry
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Life Science / Cell biology
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Life Science / Cardiovascular surgery
Papers 【 display / non-display 】
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Altered Fhod3 expression involved in progressive high-frequency hearing loss via dysregulation of actin polymerization stoichiometry in the cuticular plate. Reviewed International coauthorship
Boussaty EC, Ninoyu Y, Andrade LR, Li Q, Takeya R, Sumimoto H, Ohyama T, Wahlin KJ, Manor U, Friedman RA
PLoS genetics 20 ( 3 ) e1011211 2024.3
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS Genetics
Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed loss of the shortest row of stereocilia in the basal turn of the cochlea, and alterations in the cuticular plate surrounding stereocilia rootlets. Importantly, the hearing and HC phenotype in TG mice phenocopied that of the KO mice. These findings suggest that balanced expression of Fhod3 is critical for proper CP and stereocilia structure and function. Further investigation of Fhod3 related hearing impairment mechanisms may lend new insight towards the myriad mechanisms underlying ARHL, which in turn could facilitate the development of therapeutic strategies for ARHL.
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Hikmawan Wahyu Sulistomo, Takayuki Nemoto, Yohko Kage, Hajime Fujii, Taku Uchida, Kogo Takamiya, Hideki Sumimoto, Hiroaki Kataoka, Haruhiko Bito, and Ryu Takeya
Cerebral Cortex 31 ( 4 ) 2205 - 2219 2020.11
Authorship：Last author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Cerebral Cortex
Changes in the shape and size of the dendritic spines are critical for synaptic transmission. These morphological changes depend on dynamic assembly of the actin cytoskeleton and occur differently in various types of neurons. However, how the actin dynamics are regulated in a neuronal cell type-specific manner remains largely unknown. We show that Fhod3, a member of the formin family proteins that mediate F-actin assembly, controls the dendritic spine morphogenesis of specific subpopulations of cerebrocortical pyramidal neurons. Fhod3 is expressed specifically in excitatory pyramidal neurons within layers II/III and V of restricted areas of the mouse cerebral cortex. Immunohistochemical and biochemical analyses revealed the accumulation of Fhod3 in postsynaptic spines. Although targeted deletion of Fhod3 in the brain did not lead to any defects in the gross or histological appearance of the brain, the dendritic spines in pyramidal neurons within presumptive Fhod3-positive areas were morphologically abnormal. In primary cultures prepared from the Fhod3-depleted cortex, defects in spine morphology were only detected in Fhod3 promoter-active cells, a small population of pyramidal neurons, and not in Fhod3 promoter-negative pyramidal neurons. Thus, Fhod3 plays a crucial role in dendritic spine morphogenesis only in a specific population of pyramidal neurons in a cell type-specific manner.
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Formin homology 2 domain-containing 3 (Fhod3) controls neural plate morphogenesis in mouse cranial neurulation by regulating multidirectional apical constriction. Reviewed
Sulistomo HW, Nemoto T, Yanagita T, Takeya R
The Journal of biological chemistry 294 ( 8 ) 2924 - 2934 2018.12
Language：English Publishing type：Research paper (scientific journal)
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Interaction between cardiac myosin-binding protein C and formin Fhod3 Reviewed
Matsuyama S., Kage Y., Fujimoto N., Ushijima T., Tsuruda T., Kitamura K., Shiose A., Asada Y., Sumimoto H., Takeya R.
Proceedings of the National Academy of Sciences of the United States of America 115 ( 19 ) E4386 - E4395 2018.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America
© 2018 National Academy of Sciences. All rights reserved. Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.
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Ushijima T., Fujimoto N., Matsuyama S., Kan-O M., Kiyonari H., Shioi G., Kage Y., Yamasaki S., Takeya R., Sumimoto H.
Journal of Biological Chemistry 293 ( 1 ) 148 - 162 2018.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Biological Chemistry
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifeninduced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these agerelated changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3- deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.
Books 【 display / non-display 】
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ラング・デール薬理学 第8版
H. P. Rang, J. M. Ritter, R. J. Flower, G. Henderson, 監訳 渡邊直樹（ Role： Joint translator）
エルゼビア・ジャパン 2018.12
Language：Japanese Book type：Textbook, survey, introduction
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ラング・デール薬理学 第8版
H. P. Rang, J. M. Ritter, R. J.Flower, G. Henderson監訳 渡邊直樹（ Role： Joint translator）
エルゼビア・ジャパン 2018.12
Language：Japanese Book type：Textbook, survey, introduction
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マッキー生化学 第６版
Trudy McKee ,James R.McKee, 監修 市川 厚, 監訳 福岡 伸一（ Role： Joint translator , 第18章 遺伝情報）
化学同人 2018.3
Language：Japanese Book type：Textbook, survey, introduction
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マッキー生化学 第４版
市川 厚, 福岡 伸一 他（ Role： Joint translator , 18章 遺伝情報）
化学同人 2010.3
Language：Japanese Book type：Textbook, survey, introduction
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マッキー生化学 第3版
市川 厚，福岡 伸一 他（ Role： Joint translator , 18章 遺伝情報）
化学同人 2003.10
Language：Japanese Book type：Textbook, survey, introduction
MISC 【 display / non-display 】
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心筋サルコメアの形成とその維持機構
武谷 立
宮崎県医師会医学会誌 （別冊） 40 ( 1 ) 1 - 6 2016.3
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (other) Publisher：宮崎県医師会
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心筋の収縮装置「サルコメア」の形成の分子機構
武谷 立
生存科学 26 ( 1 ) 299 - 305 2015.9
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (other) Publisher：公益財団法人 生存科学研究所
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薬理学ロールプレイ:Case & Communication based approach によるアクティブラーニング
柳田俊彦，根本隆行，武谷 立
日本薬理学会雑誌 146 ( 2 ) 115 - 118 2015.8
Language：Japanese Publishing type：Research paper, summary (national, other academic conference) Publisher：公益社団法人 日本薬理学会
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Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells. Reviewed
Takeya R, Ueno N, Sumimoto H
Methods Enzymol. 2006
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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食細胞による微生物の取り込みと殺菌
水上 令子，武谷 立，住本 英樹
蛋白質核酸酵素 2006
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
Presentations 【 display / non-display 】
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Forminファミリータンパク質Fhod1による肺胞マクロファージの方向性細胞運動の制御
○三浦綾子，武谷 立
第96回日本薬理学会
Event date： 2022.11.30 - 2022.12.3
Language：Japanese Presentation type：Poster presentation
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心筋症におけるフォルミン蛋白質FHOD3変異の意義と分子病態
坂田鋼治, 鹿毛陽子, ○武谷立
第45回日本分子生物学会
Event date： 2022.11.30 - 2022.12.2
Language：Japanese Presentation type：Poster presentation
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肥大型心筋症の原因遺伝子FHOD3の病原性変異がもたらす機能的変化
坂田鋼治, ○鹿毛陽子, 武谷立
第95回日本生化学会大会
Event date： 2022.11.9 - 2022.11.11
Language：Japanese Presentation type：Poster presentation
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アクチン核化重合因子Fhod1の肺胞マクロファージにおける役割
○三浦綾子，實松史幸，武谷 立
第95回日本薬理学会
Event date： 2022.3.7 - 2022.3.9
Language：Japanese Presentation type：Poster presentation
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神経細胞の形態制御におけるフォルミン蛋白質Fhod3の役割
Hikmawan Wahyu Sulistomo, 根本隆行, 鹿毛陽子, ○武谷立
生体運動研究合同班会議2022
Event date： 2022.1.7 - 2022.1.9
Language：Japanese Presentation type：Oral presentation (general)
Awards 【 display / non-display 】
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平成17年度日本生体防御学会奨励賞
2005.8 日本生体防御学会
武谷 立
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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サルコメアは回転トルクを生み出すか？
Grant number：22K19407 2022.04 - 2024.03
独立行政法人日本学術振興会 科学研究費補助金 挑戦的研究（萌芽）
Authorship：Principal investigator
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異種細胞間の細胞接着装置の恒常性維持機構の解析
Grant number：21K08183 2021.04 - 2024.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
三浦 綾子、
Authorship：Coinvestigator(s)
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心筋サルコメアにおけるアクトミオシン架橋形成の制御機構
Grant number：19K07355 2019 - 2023.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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スパインにおけるアクチン重合因子Fhod3の機能解明
Grant number：18K06701 2018.04 - 2021.03
科学研究費補助金 基盤研究(C)
Authorship：Coinvestigator(s)
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サルコメアにおける心拍動依存的な恒常性維持機構とその破綻
2014.04 - 2018.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
本研究の目的は、横紋筋の収縮装置「サルコメア」の恒常性維持機構を、アクチン重合制御の観点から明らかにすると同時に、その破綻がもたらす病態を明らかにすることである。
Other research activities 【 display / non-display 】
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査読をした
2023.03
外国語雑誌査読論文
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査読をした
2023.02
外国語雑誌査読論文
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査読をした
2022.10
外国語雑誌査読論文
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査読をした
2022.03
外国語雑誌査読論文
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特別講演 共催セミナー 特別講演
2022.03
看護薬理学カンファレンス2022 in福岡 特別講演 共催セミナー 座長
Available Technology 【 display / non-display 】
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心臓機能におけるアクチン細胞骨格の生理的意義
生体機能におけるアクチン細胞骨格の生理的意義
アクチン細胞骨格を標的とした新規治療法の開発Related fields where technical consultation is available：・細胞骨格が関わる生命現象の学術的解釈へのアドバイス
・薬理学的スクリーニング法Message：・アクチンは筋収縮に関わる蛋白質ですが、カビや酵母などを含むすべての真核生物に存在し、きわめて多様な細胞現象に関わっています。その生理的意義の解明を通じて、真核生物がなぜアクチン系を採用したのか、その本質に迫りたいと考えています。