How is a mechanical stimulus, such as touch or sound, transduced by the nervous system into a physiological response? Despite the substantial progress made in characterizing the receptors underlying vision, smell, and taste, very little is known about the molecular basis of mechanotransduction. We propose to identify and characterize the molecules required for mechanotransduction in C. elegans. These molecules may prove to be useful reagents for studying mammalian behavior, for identifying candidate genes for hereditary hearing loss, and for identifying potential targets for novel pharmaceuticals in the clinical management of pain. We have identified a bifunctional C. elegans sensory neuron that responds to both a mechanical stimulus (touch) and to particular chemical repellants. We have devised assays to test the behavioral response to both of these stimuli, and we have used these assays to identify four not genes (nose touch insensitive) that are required specifically for touch sensitivity but not for chemical avoidance. Thus, these four genes may encode molecules that are directly involved in mechanotransduction. First, we will isolate new mutations in these four not genes. These new mutations will allow us to determine if these genes are required in only mechanosensory neurons, or if they are also required in other tissues. These new mutations will also facilitate the molecular cloning of these genes. Second, we will identify new not genes, and determine whether any of these new genes are specifically required for mechanotransduction. Third, we will clone those genes that seem likely to encode molecules that are directly involved in mechanotransduction. Fourth, we will determine which cells express these genes, and the subcellular distribution of each gene product. Fifth, we will attempt to demonstrate that these genes encode functional mechanoreceptors by conferring mechanosensory function on novel cells by ectopic expression of these not genes. In summary, these experiments should allow us to identify a set of genes that encode molecules that are directly involved in mechanotransduction, or which regulate the function or expression of the mechanotransduction apparatus. The identification of these molecules will provide us with the tools necessary to answer one of the enduring mysteries of neurobiology -- what are the molecular mechanisms underlying mechanosensation and modality coding of mechanical stimuli.
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