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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Genetics Study Section (GEN)
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Baughman, Robert W
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Massachusetts General Hospital
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Pym, Edward; Sasidharan, Nikhil; Thompson-Peer, Katherine L et al. (2017) Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression. Elife 6:
Tong, Xia-Jing; López-Soto, Eduardo Javier; Li, Lei et al. (2017) Retrograde Synaptic Inhibition Is Mediated by ?-Neurexin Binding to the ?2? Subunits of N-Type Calcium Channels. Neuron 95:326-340.e5
Tong, Xia-Jing; Hu, Zhitao; Liu, Yu et al. (2015) A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors. Elife 4:e09648
Hu, Zhitao; Tong, Xia-Jing; Kaplan, Joshua M (2013) UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans. Elife 2:e00967
Hu, Zhitao; Hom, Sabrina; Kudze, Tambudzai et al. (2012) Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science 337:980-4
Thompson-Peer, Katherine L; Bai, Jihong; Hu, Zhitao et al. (2012) HBL-1 patterns synaptic remodeling in C. elegans. Neuron 73:453-65
Babu, Kavita; Hu, Zhitao; Chien, Shih-Chieh et al. (2011) The immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling. Neuron 71:103-16
Simon, David J; Madison, Jon M; Conery, Annie L et al. (2008) The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell 133:903-15
Chun, Denise K; McEwen, Jason M; Burbea, Michelle et al. (2008) UNC-108/Rab2 regulates postendocytic trafficking in Caenorhabditis elegans. Mol Biol Cell 19:2682-95
Juo, Peter; Harbaugh, Tom; Garriga, Gian et al. (2007) CDK-5 regulates the abundance of GLR-1 glutamate receptors in the ventral cord of Caenorhabditis elegans. Mol Biol Cell 18:3883-93

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