The Claudin Superfamily Protein NSY-4 Biases Lateral Signaling to Generate Left-Right Asymmetry in C. elegans Olfactory Neurons

Early in C. elegans development, signaling between bilaterally symmetric AWC olfactory neurons causes them to express different odorant receptor genes. AWC left-right asymmetry is stochastic: in each animal, either the left or the right neuron randomly becomes AWC^ON, and the other neuron becomes AWC^OFF. Here we show that the nsy-4 gene coordinates the lateral signaling that diversifies AWC^ON and AWC^OFF neurons. nsy-4 mutants generate 2 AWC^OFF neurons, as expected if communication between the AWC neurons is lost, whereas overexpression of nsy-4 results in 2 AWC^ON neurons. nsy-4 encodes a transmembrane protein related to the γ subunits of voltage-activated calcium channels and the claudin superfamily; it interacts genetically with calcium channels and antagonizes a calcium-to-MAP kinase cascade in the neuron that becomes AWC^ON. Genetic mosaic analysis indicates that nsy-4 functions both cell-autonomously and nonautonomously in signaling between AWC neurons, providing evidence for lateral signaling and feedback that coordinate asymmetric receptor choice.