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

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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.