From insects to mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor target their axonal projections to specific glomerular destinations in the antennal lobe/olfactory bulb, creating an odor map in these first olfactory structures of the central nervous system. In the fly, axons of 50 classes of ORNs match precisely with the corresponding dendrites of 50 classes of second order olfactory projection neurons (PNs) to form the 50 glomeruli of the antennal lobe. Olfactory information is thus faithfully delivered from sensory organs in the periphery to higher brain centers, enabling innate and learned olfactory behavior. Thanks to the support of this grant, our studies over the past ten years have made the Drosophila antennal lobe one of the best-understood circuits in terms of the molecular, cellular, and developmental underpinnings of wiring specificity. We have provided a detailed description of the wiring process with single-cell resolution, finding that PN dendrites pre-pattern the antennal lobe prior to ORN axon invasion. We have uncovered the contributions of PN dendrite-dendrite interactions and ORN axon-axon interactions, as well as PN-ORN synaptic partner matching in the wiring process. We have identified several transcription factors and cell surface receptors that instruct wiring specificity in the above cellular contexts. We have also created novel tools to analyze wiring specificity with single-glomerular and single neuron precision. In this renewal, we propose a series of molecular genetic experiments with the aim of identifying the cell surface code that instructs the precise matching between 50 classes of ORNs and PNs. We will study cell surface proteins that regulate ORN axons in choosing their specific trajectories en route to their destined glomeruli, targeting to specific areas of the antennal lobe, and matching with specific postsynaptic partner PNs. An emphasis will be placed on RNAi-based screens to identify cell surface proteins. We will follow up with in-depth mechanistic studies to place their actions in the proper cellular and developmental context. We expect that completion of the proposed experiments in this grant will significantly enrich and expand our understanding of the logic and mechanisms of olfactory circuit assembly. These studies will contribute to our understanding of a central problem in developmental neurobiology: how wiring specificity of neural circuits is achieved during development. By uncovering the molecules and mechanisms inherent to the fly olfactory circuit, we have already provided insight into constructing more complex neural circuits in the mammalian brain, and established links between neural circuit wiring and disorders of the human brain.

Public Health Relevance

Understanding how neural circuits are assembled during normal development is a prerequisite for understanding many human neurological and psychiatric disorders that disrupt this assembly process. Indeed, some of the human versions of genes that we have discovered in flies to play important roles in neural circuit wiring are implicated in disorders of the brain, including peripheral neuropathy, bipolar disorders, and intellectual disabilities. In addition, knowledge of insect olfactory system organization and development can be used to design strategies to combat malaria, which is transmitted by mosquitos that primarily utilize olfaction to find both their mates and human hosts.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Sullivan, Susan L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Arts and Sciences
United States
Zip Code
Wu, Bing; Li, Jiefu; Chou, Ya-Hui et al. (2017) Fibroblast growth factor signaling instructs ensheathing glia wrapping of Drosophila olfactory glomeruli. Proc Natl Acad Sci U S A 114:7505-7512
Mosca, Timothy J; Luginbuhl, David J; Wang, Irving E et al. (2017) Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons. Elife 6:
Wu, Bing; Luo, Liqun; Gao, Xiaojing J (2016) Cas9-triggered chain ablation of cas9 as a gene drive brake. Nat Biotechnol 34:137-8
Riabinina, Olena; Luginbuhl, David; Marr, Elizabeth et al. (2015) Improved and expanded Q-system reagents for genetic manipulations. Nat Methods 12:219-22, 5 p following 222
Gao, Xiaojing J; Clandinin, Thomas R; Luo, Liqun (2015) Extremely sparse olfactory inputs are sufficient to mediate innate aversion in Drosophila. PLoS One 10:e0125986
Gao, Xiaojing J; Riabinina, Olena; Li, Jiefu et al. (2015) A transcriptional reporter of intracellular Ca(2+) in Drosophila. Nat Neurosci 18:917-25
Ward, Alex; Hong, Weizhe; Favaloro, Vincenzo et al. (2015) Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit. Neuron 85:1013-28
Pearce, Margaret M P; Spartz, Ellen J; Hong, Weizhe et al. (2015) Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat Commun 6:6768
Sakuma, Chisako; Kawauchi, Takeshi; Haraguchi, Shuka et al. (2014) Drosophila Strip serves as a platform for early endosome organization during axon elongation. Nat Commun 5:5180
Hong, Weizhe; Luo, Liqun (2014) Genetic control of wiring specificity in the fly olfactory system. Genetics 196:17-29

Showing the most recent 10 out of 46 publications