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. 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 have defined the biochemical role of LUSH in pheromone sensitivity. LUSH acts as an adapter that undergoes a conformational shift upon pheromone binding. This activated conformation of LUSH is what triggers receptors on T1 neurons to induce action potentials. We have generated mutants in LUSH that activate the T1 neurons in the absence of pheromone, demonstrating that the OBP and not the pheromone, is the true ligand for the neurons. 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, Or67d, 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
Pheromone-induced behavior
RECENT PUBLICATIONS
Laughlin, J. D., Ha, T.-S., Jones, D. M. N., and Smith, D. P., "Activation of Pheromone-Sensitive Neurons is Mediated by Conformational Activation of Pheromone-Binding Protein" Cell, 133:1255-1265, 2008
Jin, X., Ha, T. S., Smith, D. P., "SNMP is a Signaling Component Required for Pheromone Sensitivity in Drosophila" PNAS USA, 105:10996-1001, 2008
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., Ye, X., Strauss, T. Sanders, C. Kuhn, M., Liu, Q. and Smith, D. P., "R2D2 Regulates Follicle Cell Patterning through Interactions with DICER-1" Mechanisms of Development, 125:475-485, 2008
Kalidas, S. and Smith, D. P., "Novel Genomic cDNA Hybrids Produce Effective RNA Interference in Adult Drosophila" Neuron, 33:1-8, 2002
SIGNIFICANT PUBLICATIONS
Laughlin, J. D., Ha, T.-S., Jones, D. M. N., and Smith, D. P., "Activation of Pheromone-Sensitive Neurons is Mediated by Conformational Activation of Pheromone-Binding Protein" Cell, 133:1255-1265, 2008
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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