PT  - JOURNAL ARTICLE
AU  - Ramezan Paravitorghabeh
AU  - Dharsan Soundarrajan
AU  - Jeremiah J. Zartman
TI  - From spikes to intercellular waves: tuning the strength of calcium stimulation modulates organ size control
AID  - 10.1101/649582
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 649582
4099  - http://biorxiv.org/content/early/2019/06/03/649582.short
4100  - http://biorxiv.org/content/early/2019/06/03/649582.full
AB  - Calcium (Ca2+) signaling is a fundamental molecular communication mechanism for the propagation of information in eukaryotic cells. Cytosolic calcium ions integrate a broad range of hormonal, mechanical and electrical stimuli within cells to modulate downstream cellular processes involved in organ development. However, how the spatiotemporal dynamics of calcium signaling are controlled at the organ level remains poorly understood. Here, we show that the spatiotemporal extent of calcium signaling within an epithelial system is determined by the class and level of hormonal stimulation and by the subdivision of the cell population into a small fraction of initiator cells surrounded by a larger fraction of standby cells connected through gap junction communication. To do so, we built a geometrically accurate computational model of intercellular Ca2+ signaling that spontaneously occurs within developing Drosophila wing imaginal discs. The multi-scale computational model predicts the regulation of the main classes of Ca2+ signaling dynamics observed in vivo: single cell Ca2+ spikes, intercellular transient bursts, intercellular waves and global fluttering. We show that the tuning of the spatial extent of Ca2+ dynamics from single cells to global waves emerges naturally as a function of global hormonal stimulation strength. Further, this model provides insight into how emergent properties of intercellular calcium signaling dynamics modulates cell growth within the tissue context. It provides a framework for analyzing second messenger dynamics in multicellular systems.Significance Statement Intercellular calcium signaling is critical for epithelial morphogenesis and homeostasis. However, how cytosolic calcium concentration dynamics are regulated at the multicellular level are poorly understood. Here, we show using a novel multiscale computational model that the spatial extent of intercellular calcium communication is controlled by two factors: i) the relative strength of global hormonal stimulation, and ii) the presence of a subset of “initiator cells” among a population of “standby cells” that are connected by gap junctions. Localized multicellular calcium signals are associated with maximal organ growth while persistent calcium waves inhibit overall organ growth. This mechanism explains the broad range of spatiotemporal calcium signaling dynamics that occurs during epithelial development.