第1016回生物科学セミナー
Exploring the roles of Protocadherin 15 (Pcdh15) and Transmembrane channel-like proteins (Tmcs) in mechanotransduction of zebrafish hair cells
前田 礼男 博士（Oregon Health & Science University）
2014年11月28日(金) 17:30-18:30 理学部2号館 201号室
Hair cells are specialized sensory receptor cells of both the auditory system and the vestibular system in vertebrates. The common feature of hair cells is the hair bundle, which is the sensory organelle formed by the ordered staircase-like structure of stereocilia. Mechanical deflection of a hair bundle increases the tension of tip links that interconnect the stereocilia, and converts mechanical force into a neural signal. These tip links are thought to pull open the force-gated transduction channels, resulting in the influx of cations. To date, the identity of the mechanosensitive channels in the stereocilia is still unknown, although several candidate proteins have been proposed.
The zebrafish is a powerful model organism for studying the molecular basis of inner ear development and function. Previous studies in zebrafish have helped to elucidate the genes required for function of hair cells, including Pcdh15a. Moreover, recent studies in mammals suggest that PCDH15a is a central component of tip links and may be closely associated with the mechanotransduction channel. Here we sought to identify the proteins that interact with zebrafish Pcdh15a to determine how the tip link is coupled to the transduction complex. Using a membrane-based yeast two-hybrid screen, we identified an N-terminal fragment of Transmembrane channel-like 2a (Tmc2a). Tmc2a is an orthologue of mammalian TMC2. Recent studies reported that TMC1 and TMC2 are components of the mechanotransduction channel in mammalian hair cells. To investigate the roles of zebrafish Tmc2a in hair cells, we overexpressed N-terminal fragments of Tmc2a in hair cells to interfere with the association between Pcdh15a and Tmc2a. Upon overexpression, we detected mislocalization of Pcdh15a in hair bundles and significant decreases in responses to mechanical stimuli. These results suggest that the interaction between Pcdh15a and Tmc2a is critical for mechanotransduction in zebrafish hair cells. Taken together with previous studies in mammals, our data support the idea that TMC1 and TMC2 are key components of the mechanotransduction complex in auditory/vestibular hair cells.
In this seminar, I will present recent progress and discuss the key findings in understanding the molecular mechanisms of mechanotransduction of hair cells in vertebrates.
Reference:
Maeda R, Kindt KS, Mo W, et al. (2014) Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc Natl Acad Sci USA. vol.111, 12907-12912
