Post Doctoral Fellow

Chemistry and Biochemistry

Howard Hughes Medical Institute

University of California, Los Angeles (Los Angeles, CA)

Larry Zipursky

I am interested in molecular mechanisms that regulate assembly and specialization of sensory circuits, and how changes in circuitry mediates emergence and evolution of species-specific behaviors.

I use the olfactory system of the fruit fly Drosophila melanogaster, which has proved to be an excellent system amenable to genetic manipulation and structural visualization of this sensory circuitry. I have carried out an unbiased histology-based mutagenesis screen in search of molecules that are required for the organization in the Drosophila olfactory system, and found a variety of genes affecting different aspects of the olfactory circuitry. Initially I focused on one of these mutants, miR-279, which specifically affected the olfactory circuitry responsible for CO2 detection in flies. CO2 elicits different olfactory behaviors across species. In Drosophila, detection of CO2 is accomplished using two evolutionarily conserved receptors (Gr21a/Gr63a) expressed on a subset of antennal neurons. These neurons project to a ventral glomerulus in the antennal lobe and activation of this circuitry results in an avoidance response. By contrast, in mosquito CO2 neurons are located in the maxillary palps (MP), connect to medial sites in the antennal lobe and promote attraction. During my postdoctoral work, I found that loss of Drosophila miR-279, leads to formation of ectopic CO2 neurons in the MP. miR-279 is expressed in the MP sensory organ precursor cells and here it acts in the non-neuronal precursors through down-regulation of the transcription factor, Nerfin-1. Despite the fact that CO2 neurons in miR-279 mutant maxillary palps are functional, that is they express the CO2 receptor complex, Gr21a/Gr63a, make connections to the ventral glomerulus, and physiologically can detect CO2, they are hybrid neurons. They simultaneously express the wiring and receptor properties of either Or42a or Or59c, the only two MP ORN classes that target medial glomeruli in the antennal lobe. This is an interesting phenomenon given the mosquitoes that use CO2 as an attractive odor, the CO2 neurons also target to a analogous medial glomeruli. Previously, we had proposed that this is a putative evolutionary intermediate state of a CO2 neuronal population, before their elimination from the MP in Drosophila. We hypothesize that natural selection can work on such an evolutionary intermediate to generate different combinations of OR, wiring, and cellular positional specificities, depending on the selective pressures that the insect is exposed to in its environment. For example, it can match up either a CO2 or an Or42a receptor program with medial targeting program, or a CO2 receptor program with a ventral targeting program. This mechanism may lead to novel olfactory responses to either the same odorant, such as attraction versus repulsion, or to different odorants, in different species. In addition, despite the fact that receptor expression or connectivity choice are independent events, the hybrid neurons expose a genetic program utilized to couple these events at a distinct step during the development of a given ORN. Recently I have also been focusing on another mutant we isolated from the screen, that phenocopies the miR-279 phenotype. The current working hypothesis is that ig2227 is upstream of miR-279, and it directly or indirectly regulates its expression.