Mechanical stimuli, such as sound, touch, stretch and gravity, activate mechanosensory neurons that mediate mechanosensory modalities such as hearing, proprioception, touch, and blood pressure regulation. The central player in mechanosensation is the mechanotransduction channel that detects mechanical forces and transduces them into electrical outputs. Remarkably, in addition to neurons, many other cell types, such as those in the bone, muscle, kidney and eye, also respond to various mechanical stimuli. Despite the prevalence of mechanotransduction channels, few such channels have been identified in mammals. Apparently, novel types of mechanotransduction channels must be present in mammals but remain to be identified. In particular, the molecular identity of the mechanotransduction channel mediating hearing in mammals remains obscure and highly controversial. The development of new strategies and new model systems may facilitate the identification of novel types of mechanotransduction channels. C. elegans represents a valuable genetic model for the study of sensory biology. To survive and thrive in the harsh environment, worms have evolved a rich repertoire of sensory systems that allow them to sense and react to odor, tastant, touch and light, covering four out of the five primary sensory modalities. More importantly, the genes encoding sensory receptors and channels tend to be evolutionarily conserved in worms. This, together with its short generation time (~3 days) and facile genetic tools, makes C. elegans an ideal system for identifying novel sensory receptors and channels. Nevertheless, worms are considered insensitive to sound. Here, we propose to develop C. elegans as a new model for studying sound sensation and the underlying neural and genetic mechanisms. To do so, we will take a multidisciplinary approach combining molecular genetics, behavioral analysis, functional imaging, and electrophysiology. As sensory receptors and channels tend to be evolutionarily conserved in C. elegans, the proposed work will provide novel insights into our understanding of sound sensation in mammals. On a broader perspective, as many cell types are mechanosensitive, yet only a few mechanotransduction channels have been cloned, the proposed work will also facilitate the identification of novel mechanotransduction channels mediating other mechanosensory modalities (e.g. touch, proprioception, blood pressure regulation, etc.) in mammals.
Defects in mechanosensation lead to a variety of neurological diseases such as hearing loss and neuropathic pain that affect over a billion people worldwide. The proposed work will facilitate our understanding of mechanosensory transduction in humans and how its defects lead to diseases.
