Neural and genetic mechanisms underlying mechanosensation in C. elegans - Mechanical cues, such as sound, touch, gravity, and shear stress, activate mechanosensory neurons/cells that mediate mechanosensory modalities such as hearing, touch, proprioception, shear stress sensation, and blood pressure regulation. A central player in mechanosensation is the mechanotransduction channels that sense mechanical forces and transduce them into electrical outputs. Among the six primary sensory modalities, auditory sensation or hearing is unique in that it is only found in vertebrates and some insects. The vast majority of invertebrate species are thus considered insensitive to sound. We recently challenged this conventional view by showing that C. elegans senses airborne sound at frequencies between 100 Hz and 5 kHz. Sound vibrates the worm skin that acts as a pressure-to-displacement transducer similar to vertebrate eardrum, activates sound-sensitive neurons attached to the skin, and evokes phonotaxis behavior. Thus, the ability to sense sound is not restricted to vertebrates and insects as previously thought. Our work also developed C. elegans as a new model for studying auditory sensation. To interrogate the underlying genetic mechanisms, we conducted a large genetic screen for genes regulating auditory sensation in C. elegans. We found that the nAChR DES-2/DES-3, an ACh-gated cation channel, transduces sound signals in sound- sensitive neurons and does so independently of ACh. Our genetic screen also identified several other genes, such as pnpt-1, whose human homolog PNPT1 has been identified as a nonsyndromic deafness gene with an unknown etiology. These findings uncover a novel, unexpected function of nAChRs in mechanosensation, suggesting that nAChRs may participate in the formation of a novel mechanotransduction channel. In addition, the identification of a conserved role of pnpt-1/PNPT1 in both C. elegans and human auditory sensation reveals the presence of similarities in genetic mechanisms underlying auditory sensation across phyla. Thus, investigating auditory sensation in C. elegans will help characterize not only those mechanisms conserved across phyla (e.g. pnpt-1/PNPT1), but also phylum-specific mechanisms (e.g. nAChRs), the latter of which may lead to the identification of novel mechanotransduction channels mediating other mechanosensory modalities in mammals, such as touch, proprioception, shear stress sensation, blood pressure regulation, etc. Despite these exciting findings, many unanswered questions remain. For example, the molecular composition of the mechanotransduction channel mediating auditory sensation in C. elegans remains unclear. In addition, though we identified a key role for pnpt-1PNPT1 in auditory sensation, the underlying mechanisms remain elusive. We will address these questions in the current proposal using a multidisciplinary approach combining molecular genetics, behavioral analysis, calcium imaging and electrophysiology. The proposed work will not only provide novel insights into auditory sensation but also mechanosensation as a whole.
