Toll receptors wire the olfactory circuit

Science Signaling  10 Mar 2015:
Vol. 8, Issue 367, pp. ec53
DOI: 10.1126/scisignal.aab0682

Assembly of neuronal circuits involves connections between growing axons and dendrites of different neuron groups during development. Specific connections between olfactory receptor neuron (ORN) axons and projection neuron (PN) dendrites mediate the sense of smell. Toll receptors and Toll-like receptors (TLRs) comprise a nine-member family of single-pass transmembrane proteins. In flies, the Toll family is best known for regulating dorsal-ventral polarity, and in mammals, TLRs mediate the innate immune response to microbes. Using an RNA-interference screen and four-color confocal imaging in transgenic Drosophila melanogaster, Ward et al. found that Toll-family receptors Toll-6 and Toll-7 instruct wiring specificity in the olfactory circuit. Whole-body knockdown or loss-of-function mutation of Toll-6 or Toll-7 caused dorsal or medial mistargeting of ORN axons, respectively. In ORN-specific Toll-7 loss-of-function mutants, axon targeting was rescued by re-expression of Toll-7 in ORNs. In mosaic ORN-specific mutant flies, wild-type ORNs retained proper targeting to PN dendrites, suggesting that ORN axons required Toll-7 function for proper targeting. Whereas Toll-7 was abundant predominantly in ORN axons, Toll-6 was present in ORN axons and PN dendrites. Cell type-specific Toll-6 knockdown and re-expression showed that Toll-6 acts primarily in PNs to direct ORN axon targeting. Knocking down Toll-6 specifically in PNs also disrupted PN dendrite targeting. There are 50 classes of ORNs and PNs, and some classes did not have Toll-7 or Toll-6, respectively. Introduction of Toll-6 or Toll-7 in these Toll-6/7-negative ORNs or PNs induced mistargeting toward regions to which their Toll-6/7-positive counterparts project, suggesting that Toll-6 and Toll-7 play instructive roles in axon and dendrite targeting. Introduction of Toll-2 or Toll-8, which are closest in sequence similarity to Toll-6 and Toll-7, into ORNs also produced ORN axon mistargeting. Introduction of Toll-7 in PNs rescued targeting defects in Toll-6 knockdowns, suggesting that Toll-7 could substitute for Toll-6 in PNs. The function of Toll-6 or Toll-7 in ORN-PN wiring did not require canonical Toll receptor ligands, downstream partners, or either receptor’s cytoplasmic domains. These findings reveal that Toll receptors mediate olfactory circuit assembly in flies and suggest that another signaling mechanism for these receptors remains to be discovered.

A. Ward, W. Hong, V. Favaloro, L. Luo, Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit. Neuron 85, 1013–1028 (2015). [PubMed]