Understanding the role of Tmc proteins in hair cell mechanotransduction of zebrafish

项目总结 斑马鱼模型系统有效地提供了对听力、耳聋、 和毛细胞功能。它的成功部分在于与听力相关的形态和基因组的相似性 在斑马鱼和哺乳动物之间。显然，在细胞水平上，毛细胞的形态是相似的，它的 签名细胞器是保守的。在哺乳动物和斑马鱼中，发束具有不同高度的立体纤毛。 在分子水平上，立体纤毛通过末端连接连接在一起，从而实现机械转导。众多基因 当突变时会导致人类或小鼠耳聋，也会导致鱼类耳聋或毛细胞功能障碍。 TMCs突变导致人类耳聋DFNB7/11和DFNA36，以及人类毛细胞缺陷 斑马鱼的侧线和耳朵。对小鼠和斑马鱼TMCs的研究表明，不同的毛细胞含有 器官需要不同的TMC蛋白或TMC蛋白的组合来执行其特定的任务 并对不同类型的机械刺激进行编码。此外，同一器官内的毛细胞可以有不同的 TMC要求。例如，侧线神经肥大器官内的一些毛细胞需要Tmc2a和其他 需要Tmc2a和Tmc2b；这表明这些蛋白质可能共同作用于机械转导 这可能会改变这一过程的质量。此外，有证据表明，所有的TMC并不是等同的。 这些器官在它们表达和运行所需的TMC方面有何不同，以及原因 这些差异目前尚不清楚。在这里，我们将研究TMCs在毛细胞中的作用 斑马鱼的机械转导。在具体目标1中，我们将确定TMCs对斑马鱼的贡献是否不同 听证。在特定的目标2中，我们将确定TMCs在毛细胞机械转导和侧线- 居间行为。在具体目标3中，我们将确定TMCs是否在体内相互作用。这些研究应该 让我们更深入地了解毛细胞如何使用特定的TMC来编码听觉和行为的刺激。

PROJECT SUMMARY The zebrafish model system has effectively offered insights into the molecular mechanisms of hearing, deafness, and hair cell function. Its success partly lies in the morphological and genomic similarities related to hearing between zebrafish and mammals. Explicitly, at the cellular level, the morphology of the hair cell is similar and its signature organelles are conserved. In mammals and zebrafish, the hair bundle has stereocilia of graded heights. At the molecular level, the stereocilia are joined by tip links to permit mechanotransduction. Numerous genes that when mutated cause deafness in humans or mice, also cause deafness or hair cell dysfunction in fish. Mutations in TMCs cause deafness forms DFNB7/11 and DFNA36 in humans and defects in the hair cells of the lateral line and ear in zebrafish. Studies on mouse and zebrafish Tmcs indicate that different hair cell-containing organs require different Tmc proteins or combinations of Tmc proteins to carry out their specific task in receiving and encoding different types of mechanical stimuli. Moreover, hair cells within the same organ can have different Tmc requirements. For instance, some hair cells within a lateral line neuromast organ require Tmc2a and others require both Tmc2a and Tmc2b; this indicates that these proteins may work together for mechanotransduction and this could change the quality of this process. Moreover, there is evidence that all Tmcs are not equivalent. How the organs differ in terms of the Tmcs that they express and require for functioning and the reasons for these differences are currently unknown. Here, we will examine the roles of Tmcs in hair cell mechanotransduction in zebrafish. In Specific Aim 1, we will determine if Tmcs contribute differently to zebrafish hearing. In Specific Aim 2, we will determine the role of Tmcs in hair cell mechanotransduction and lateral line- mediated behavior. In Specific Aim 3, we will determine whether Tmcs interact in vivo. These studies should allow a deeper understanding of how hair cells use particular Tmcs to encode stimuli for hearing and behavior.