The wavy Mutation Maps to the Inositol 1,4,5-Trisphosphate 3-Kinase 2 (IP3K2) Gene of Drosophila and Interacts with IP3R to Affect Wing Development

Inositol 1,4,5-trisphosphate (IP₃) regulates a host of biological processes from egg activation to cell death. When IP₃-specific receptors (IP3Rs) bind to IP₃, they release calcium from the ER into the cytoplasm, triggering a variety of cell type- and developmental stage-specific responses. Alternatively, inositol polyphosphate kinases can phosphorylate IP₃; this limits IP3R activation by reducing IP₃ levels, and also generates new signaling molecules altogether. These divergent pathways draw from the same IP₃ pool yet cause very different cellular responses. Therefore, controlling the relative rates of IP3R activation vs. phosphorylation of IP₃ is essential for proper cell functioning. Establishing a model system that sensitively reports the net output of IP₃ signaling is crucial for identifying the controlling genes. Here we report that mutant alleles of wavy (wy), a classic locus of the fruit fly Drosophila melanogaster, map to IP₃ 3-kinase 2 (IP3K2), a member of the inositol polyphosphate kinase gene family. Mutations in wy disrupt wing structure in a highly specific pattern. RNAi experiments using GAL4 and GAL80^ts indicated that IP3K2 function is required in the wing discs of early pupae for normal wing development. Gradations in the severity of the wy phenotype provide high-resolution readouts of IP3K2 function and of overall IP₃ signaling, giving this system strong potential as a model for further study of the IP₃ signaling network. In proof of concept, a dominant modifier screen revealed that mutations in IP3R strongly suppress the wy phenotype, suggesting that the wy phenotype results from reduced IP₄ levels, and/or excessive IP3R signaling.

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