From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control

Information flow within and between cells depends significantly on calcium (Ca(2+)) signaling dynamics. However, the biophysical mechanisms that govern emergent patterns of Ca(2+) signaling dynamics at the organ level remain elusive. Recent experimental studies in developing Drosophila wing imaginal discs demonstrate the emergence of four distinct patterns of Ca(2+) activity: Ca(2+) spikes, intercellular Ca(2+) transients, tissue-level Ca(2+) waves, and a global “fluttering” state. Here, we used a combination of computational modeling and experimental approaches to identify two different populations of cells within tissues that are connected by gap junction proteins. We term these two subpopulations “initiator cells,” defined by elevated levels of Phospholipase C (PLC) activity, and “standby cells,” which exhibit baseline activity. We found that the type and strength of hormonal stimulation and extent of gap junctional communication jointly determine the predominate class of Ca(2+) signaling activity. Further, single-cell Ca(2+) spikes are stimulated by insulin, while intercellular Ca(2+) waves depend on Gαq activity. Our computational model successfully reproduces how the dynamics of Ca(2+) transients varies during organ growth. Phenotypic analysis of perturbations to Gαq and insulin signaling support an integrated model of cytoplasmic Ca(2+) as a dynamic reporter of overall tissue growth. Further, we show that perturbations to Ca(2+) signaling tune the final size of organs. This work provides a platform to further study how organ size regulation emerges from the crosstalk between biochemical growth signals and heterogeneous cell signaling states.