Science 345, 313–317 (2014)

In Caenorhabditis elegans, the insulin-PI3K signaling system controls nervous system function, including associative learning. In a basic assay of associative learning, worms are attracted to specific concentrations of salt if they have been previously exposed to it during a meal, but they avoid those concentrations previously associated with concomitant starvation. To understand the regulation and function of the insulin-PI3K system in this C. elegans taste-avoidance learning system, Ohno et al. first looked at mutants of various components of the signaling pathway, including that of the insulin receptor, DAF-2. They also looked at mutants in casy-1, which encodes a cadherin superfamily membrane protein implicated in learning. Both sets of mutants displayed impaired associative learning. Using RT-PCR, the authors found a daf-2 splice variant, daf-2c, which represents the insertion of an additional exon within daf-2a that is predicted to lengthen the DAF-2a protein's extracellular region. daf-2c (but not daf-2a) could complement the defect in taste-avoidance learning as well as the increased salt-induced synaptic release associated with daf-2 mutants. DAF-2a localized to the cell body, whereas DAF-2c was localized in neuronal axons in the salt-sensing gustatory neuron ASER, and this localization was dependent on CASY-1 and was increased upon starvation. The authors also found that CASY-1 acts as a direct link between DAF-2c and kinesin, playing a part in axonal localization of DAF-2c. Finally, the authors found that ERK/MAPK pathway components may transmit food signals through CASY-1 and kinesin to regulate axonal localization and therefore the function of DAF-2c.