Diversification of the mechanotransduction complex in vestibular hair cells

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Abstract The vestibular system utilizes specialized hair cells for sensing gravity and head motions. Vestibular hair cells have been broadly characterized into two cell types: Type I and Type II. Clear differences also exist among the zones of vestibular organs, consisting of a central zone surrounded by a peripheral zone of hair cells. How the mechanotransduction machinery varies across these two cell types or zones is poorly understood. Existing evidence suggests that the striolar (central) versus extrastriolar (peripheral) zones serve different functions such as sensing high versus low frequencies. How these functional differences are achieved at the molecular level is not clear. The aim of this proposal is to characterize the mechanotransduction complex in the different hair cells and zones of the utricle, a vestibular organ that is vital for sensing gravity and head motions. We have preliminary data that demonstrate differential expression of transcripts encoding a key component of the mechanotransduction complex: transmembrane channel-like proteins (TMC1 and TMC2). In zebrafish and the mouse, both Tmc1 and Tmc2 genes are expressed in regional gradients that correlate with the striolar and extrastriolar zones of the utricle. We aim to determine the dynamic developmental and adult patterns of Tmc1/2 expression along with other members of the mechanotransduction complex. We also intend to correlate these expression patterns with hair bundle morphology and hair cell physiology. In addition, we will examine these features of TMC expression and other components of the mechanotransduction complex in human utricular hair cells. Determining the extent of conservation of these features among species will be essential for the interpretation of animal models and how they inform approaches to regeneration of vestibular hair cells or other therapeutic methods for vestibular dysfunction in human patients.