Roles of Rho-family small GTPases in establishment and maintenance for hearing and balancing

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kobe University
• Principal Investigator: Ueyama Takehiko 神戸大学, バイオシグナル総合研究センター, 准教授 (80346254)
• Co-Investigator(Renkei-kenkyūsha): SAITO Naoaki 神戸大学, バイオシグナル総合研究センター, 教授 (60178499)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 聴覚 / 平衡覚 / 低分子量G蛋白質 / 聴毛 / 耳石 / DIA1 / DFNA1 / 感音難聴

Outline of Final Research Achievements

(1) We generated inner ear hair cell (HC)-specific KO mice to analyze the role of Cdc42 in HCs. HCs of Cdc42-KO mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies. Adenovirus-encoded GFP-Cdc42 expression in HCs and fluorescence resonance energy transfer (FRET) imaging of HCs from transgenic mice expressing Cdc42-FRET biosensor indicated Cdc42 presence/activation at stereociliary membranes in cochlear HCs.
(2) We found that the amount of active RhoA (GTP-form) is increased in Cdc42-KD cells. DIA1 is a downstream molecule of RhoA signaling pathways, and nucleates and elongates unbranched/straight actin. We discovered a novel patient-derived DIAPH1 mutation (c.3610C>T) in two unrelated Japanese families. Mice expressing the DIA1(R1204X) mutant experienced progressive deafness beginning at high　frequencies and HC loss with various morphological abnormalities in stereocilia at the basal turn.

Free Research Field

神経科学