听觉内毛细胞带状突触的突触囊泡对接和融合离不开自由的囊泡内C端奥托费林。

IF 6.7 2区 医学 Q1 NEUROSCIENCES
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引用次数: 0

摘要

奥托费林是内毛细胞(IHCs)突触传递中的主要钙离子传感器,但我们对奥托费林如何促进突触小泡(SV)贩运的整体动态的了解仍然有限。为了解决这个问题,我们生成了一种表达ottoferlin-GFP蛋白的基因敲入小鼠模型,其中GFP融合在其C端跨膜结构域上。与野生型蛋白类似,GFP标记的ottoferlin表现出正常表达,并与IHC SV相关。令人惊讶的是,杂合子Otof +/GFP小鼠表现出正常的听力功能,而同合子Otof GFP/GFP小鼠则是深度耳聋,原因是SV外渗严重减少。光漂白后的荧光恢复显示,在Otof GFP/GFP IHCs中,与Otof-GFP相关的SV的移动部分明显增加。相应地,带状突触的三维电子断层扫描显示,附着在带状活性区的 SV 密度降低。总之,这些结果表明,奥托费林需要一个自由的囊泡内C端来实现正常的SV对接和融合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A free intravesicular C-terminal of otoferlin is essential for synaptic vesicle docking and fusion at auditory inner hair cell ribbon synapses

Our understanding of how otoferlin, the major calcium sensor in inner hair cells (IHCs) synaptic transmission, contributes to the overall dynamics of synaptic vesicle (SV) trafficking remains limited. To address this question, we generated a knock-in mouse model expressing an otoferlin-GFP protein, where GFP was fused to its C-terminal transmembrane domain. Similar to the wild type protein, the GFP-tagged otoferlin showed normal expression and was associated with IHC SV. Surprisingly, while the heterozygote Otof +/GFP mice exhibited a normal hearing function, homozygote Otof GFP/GFP mice were profoundly deaf attributed to severe reduction in SV exocytosis. Fluorescence recovery after photobleaching revealed a markedly increased mobile fraction of the otof-GFP-associated SV in Otof GFP/GFP IHCs. Correspondingly, 3D-electron tomographic of the ribbon synapses indicated a reduced density of SV attached to the ribbon active zone. Collectively, these results indicate that otoferlin requires a free intravesicular C-terminal end for normal SV docking and fusion.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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