Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function.
Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function.
复制标题
DOI：
10.1038/s41598-018-29709-8
复制
发表时间：
2018-08-14
影响因子：
4.6
通讯作者：
Griffith AJ
中科院分区：
文献类型：
--
作者：
Nakanishi H;Kurima K;Pan B;Wangemann P;Fitzgerald TS;Géléoc GS;Holt JR;Griffith AJ
小鼠Tmc 1和Tmc 2是耳蜗和前庭毛细胞感觉传导所必需的。纯合子Tmc 1/小鼠耳聋，Tmc 2/小鼠听力正常，双纯合子Tmc 1/; Tmc 2/小鼠耳聋和严重的前庭功能障碍。这些表型与其不同的时空表达模式相一致。Tmc 1表达在耳蜗和前庭毛细胞中是持久的，而Tmc 2表达在耳蜗毛细胞中是短暂的，但在前庭毛细胞中是持久的。基于这些发现，我们假设Tmc 2在成熟耳蜗毛细胞中的持续表达可以恢复Tmc 1 β/β小鼠的听觉功能。为了在成熟耳蜗毛细胞中表达Tmc 2，我们产生了转基因小鼠品系Tg[PTmc 1：：Tmc 2]，其中Tmc 2 cDNA在Tmc 1启动子的控制下表达。Tg[PTmc 1：：Tmc 2]转基因轻微但显著地恢复了年轻Tmc 1 α/β小鼠的听力，尽管听力阈值随着年龄的增长而升高。听阈的升高与内毛细胞感觉传导的恶化和外毛细胞功能的丧失有关。虽然感觉传导保留在外毛细胞中，但它们的静纤毛最终退化。这些结果表明Tmc 1和Tmc 2在成熟耳蜗毛细胞中的不同作用和要求。
Mouse Tmc1 and Tmc2 are required for sensory transduction in cochlear and vestibular hair cells. Homozygous Tmc1∆/∆ mice are deaf, Tmc2∆/∆ mice have normal hearing, and double homozygous Tmc1∆/∆; Tmc2∆/∆ mice have deafness and profound vestibular dysfunction. These phenotypes are consistent with their different spatiotemporal expression patterns. Tmc1 expression is persistent in cochlear and vestibular hair cells, whereas Tmc2 expression is transient in cochlear hair cells but persistent in vestibular hair cells. On the basis of these findings, we hypothesized that persistent Tmc2 expression in mature cochlear hair cells could restore auditory function in Tmc1∆/∆ mice. To express Tmc2 in mature cochlear hair cells, we generated a transgenic mouse line, Tg[PTmc1::Tmc2], in which Tmc2 cDNA is expressed under the control of the Tmc1 promoter. The Tg[PTmc1::Tmc2] transgene slightly but significantly restored hearing in young Tmc1∆/∆ mice, though hearing thresholds were elevated with age. The elevation of hearing thresholds was associated with deterioration of sensory transduction in inner hair cells and loss of outer hair cell function. Although sensory transduction was retained in outer hair cells, their stereocilia eventually degenerated. These results indicate distinct roles and requirements for Tmc1 and Tmc2 in mature cochlear hair cells.
登录
查看更多内容
影响因子：
3.3
作者：
Nemzou, R. M.;Bulankina, A. V.;Moser, T.
通讯作者：
Moser, T.
影响因子：
4.6
作者：
Asai Y;Pan B;Nist-Lund C;Galvin A;Lukashkin AN;Lukashkina VA;Chen T;Zhou W;Zhu H;Russell IJ;Holt JR;Géléoc GSG
通讯作者：
Géléoc GSG
影响因子：
30.8
作者：
Kurima, K;Peters, LM;Griffith, AJ
通讯作者：
Griffith, AJ
影响因子：
2.8
作者：
DANNHOF, BJ;BRUNS, V
通讯作者：
BRUNS, V
影响因子：
15.9
作者：
Kawashima, Yoshiyuki;Geleoc, Gwenaelle S. G.;Griffith, Andrew J.
通讯作者：
Griffith, Andrew J.