(42d) From Spikes to Intercellular Waves: Tuning Intercellular Ca2+ Signaling Dynamics Modulates Organ Size Control

Calcium (Ca²⁺) signaling is a fundamental and highly conserved module for the propagation of information in eukaryotic cells. However, the biophysical mechanism that govern the dynamics of calcium signaling in cell systems such as epithelial tissues remain elusive. Recent experimental studies in developing Drosophila wing imaginal discs, a premier model for studying cell signaling during epithelial development, revealed four spatiotemporal classes of Ca²⁺ activity occurring on a tissue level. These include single-cell Ca²⁺ spikes, intercellular calcium transients, propagating tissue-level Ca²⁺ waves, and a global “fluttering” state. Here, we used a combination of computational modeling and experimental approaches to infer the presence of two separate cell states within an epithelial system, which form a network connected through gap junctional proteins. These two cellular states are termed the initiator cell and standby cell classes. Initiator cells are defined to exhibit elevated levels of Phospholipase C activity and produce more inositol trisphosphate, a key molecule that triggers the release of Ca²⁺ from the endoplasmic reticulum into the cytosol. Simulation predictions confirmed by experiments demonstrate that the strength of hormonal stimulation and the fraction of initiator cells jointly regulate the transitions between classes of Ca²⁺ signaling activity in a tissue. Further, single-cell Ca²⁺ spikes are stimulated by insulin signaling while intercellular calcium waves are dependent upon levels of Gq activity. Phenotypic analysis of perturbations to Gq signaling compared to insulin signaling supports a model where Ca²⁺ signaling provides feedback into organ growth control: Ca²⁺ signaling dynamics provide a readout of the growth state of a tissue, and perturbations impacting calcium signaling tune the final size of organs. Systems identification of the feedback properties of calcium signaling are a first step towards engineering calcium signaling dynamics in a range of tissue engineering applications.