Identifying molecular instructions to hard-wire a sensory neuron’s synaptic connectivity

The neural circuitry underlying innate behaviours must be pre-specified using precise molecular instructions. However, it is not clear what specific molecules are required to generate one neuron’s wiring pattern that make it distinct from a neighboring neuron’s wiring pattern. Here, we repeatedly sequenced three identified Drosophila sensory neurons that each have a unique and stereotyped hard-wired synaptic connectivity, to determine the cell surface molecules that distinguish their identities. Repeated sequencing of the same neuron between different animals revealed that the variability of transcription is < 1%. We find that less than 100 cell surface molecules can distinguish between a mechanosensory neuron from a chemosensory neuron. Functional characterization of the cell surface receptors verified their different roles in axonal and synaptic targeting. Finally, we expressed combinations of the different cell surface receptors to mis-wire the chemosensory neuron and increase its axonal branching.