My goal is to understand the molecular and cellular basis of odorant detection and recognition. We are utilizing the relatively simple chemosensory model system, Drosophila melanogaster, to understand the basic principles of chemosensory transduction and information processing in order to gain insight into more complicated systems like our own. We are using a combination of genetics, biochemistry, molecular biology and electrophysiology to achieve these goals. We are currently pursuing studies with two gene families that encode products essential for normal behavioral responses to odorants. The odorant-binding proteins are low molecular weight proteins expressed by non-neuronal cells and secreted into the fluids that bathe the olfactory neuron dendrites. We identified a new member of this family, LUSH and generated the first odorant-binding protein mutant by recovering mutant alleles of this gene. Remarkably, the LUSH mutants are abnormally attracted to high concentrations of ethanol, propanol and butanol, and these changes correlate with loss of inhibition of a subset of neurons in T2 sensilla. LUSH is expressed exclusively in T1 and T2 trichoid sensilla, and loss of LUSH in T1 sensilla results in complete loss of sensitivity to the male-specific pheromone, 11-cis vacceyl acetate. We are now defining the biochemical role of LUSH. The second gene family we are studying are the Drosophila odorant receptors. These are members of the seven-transmembrane, G-protein-coupled receptor family. We are using a combination of mutant analysis and transgenic flies expressing reporter genes to elucidate the functional organization of this sensory array. We recently identified a receptor that is expressed exclusively in T1 sensilla and is necessary and sufficient to confer VA sensitivity on T2 neurons when mis-expressed there. Using a genetics screen, we are identifying additional components of the pheromone signaling pathway.
We have recently discovered an effective way to suppress expression of specific genes in Drosophila using RNA interference (RNAi). We are exploiting this technology to mimic mutations in Drosophila genes with potential roles in olfaction, and to undertake a genetic dissection of RNAi itself.
RESEARCH INTERESTS
Olfactory Signal Transduction Mechanisms
RNA Interference
Odorant-Binding Proteins
Pheromone
RECENT PUBLICATIONS
Ha, T.-S., Smith, D.P., "A Pheromone Receptor Mediates 11-cis-Vaccenyl Acetate Responses in Drosophila" J. Neuroscience, 26:8727-8733, 2006
Kalidas, S., Liu, Q., Rand, T., Wang X-D., and Smith, D. P., "R2D2 Regulates Female Fertility through Interactions with DICER-1" Mechanisms of Development, submitted
Xu, P.-X., Atkinson, R., Jones, D.M.N. and Smith, D. P., "Drosophila OBP LUSH is required for Activity in Pheromone-Sensitive Neurons" Neuron, 45:193-200, 2005
Liu, Q., Rand, T. A., Kalidas, S., Du, F., Kim, H.-E., Smith, D. P., Wang, X-D., "R2D2, a bridge between the initiation and effector steps of the Drosopihla RNAi pathway" Science, 301:1925-1930, 2003
Kalidas, S. and Smith, D. P., "Novel Genomic cDNA Hybrids Produce Effective RNA Interference in Adult Drosophila" Neuron, 33:1-8, 2002
SIGNIFICANT PUBLICATIONS
Kruse, S. W., Zhao, R., Smith, D. P. and Jones, D. N. M., "Structure of a specific alcohol-binding site defined by the Drosophila protein LUSH" Nature Structural Biology, in press
Kalidas, S. and Smith, D.P., "Novel Genomic cDNA Hybrids Produce Effective RNA Interference in Adult Drosophila" Neuron, 33:1-8, 2002
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