Information flow within and between cells depends significantly on calcium (Ca2+) signaling dynamics. However, the biophysical mechanisms that govern emergent patterns of Ca2+ 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 Ca2+ activity: Ca2+ spikes, intercellular Ca2+ transients, tissue-level Ca2+ 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 Ca2+ signaling activity. Further, single-cell Ca2+ spikes are stimulated by insulin, while intercellular Ca2+ waves depend on Gαq activity. Our computational model successfully reproduces how the dynamics of Ca2+ transients varies during organ growth. Phenotypic analysis of perturbations to Gαq and insulin signaling support an integrated model of cytoplasmic Ca2+ as a dynamic reporter of overall tissue growth. Further, we show that perturbations to Ca2+ 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.
The development of an organism from an undifferentiated single cell into a spatially complex structure requires spatial patterning of cell fates across tissues. Positional information, proposed by Lewis Wolpert in 1969, has led to the characterization of many components involved in regulating morphogen signaling activity. However, how morphogen gradients are established, maintained, and interpreted by cells still is not fully understood. Quantitative and systems‐based approaches are increasingly needed to define general biological design rules that govern positional information systems in developing organisms. This short review highlights a selective set of studies that have investigated the roles of physiological signaling in modulating and mediating morphogen‐based pattern formation. Similarities between neural transmission and morphogen‐based pattern formation mechanisms suggest underlying shared principles of active cell‐based communication. Within larger tissues, neural networks provide directed information, via physiological signaling, that supplements positional information through diffusion. Further, mounting evidence demonstrates that physiological signaling plays a role in ensuring robustness of morphogen‐based signaling. We conclude by highlighting several outstanding questions regarding the role of physiological signaling in morphogen‐based pattern formation. Elucidating how physiological signaling impacts positional information is critical for understanding the close coupling of developmental and cellular processes in the context of development, disease, and regeneration.
Calcium (Ca 2+ ) 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 Ca 2+ signaling that spontaneously occurs within developing Drosophila wing imaginal discs. The multi-scale computational model predicts the regulation of the main classes of Ca 2+ signaling dynamics observed in vivo: single cell Ca 2+ spikes, intercellular transient bursts, intercellular waves and global fluttering. We show that the tuning of the spatial extent of Ca 2+ 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. Second messengers | Gap junction communication | Spatiotemporal patterns | Information processing | Hopf bifurcation. C alcium ions (Ca 2+ ) mediate a large number of physi-1 ological and regulatory processes such as proliferation, 51 Significance StatementIntercellular 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.The experimental data is imaged by Dharsan Soundarrajan 2 .these results support a novel model that links tissue-level 52 calcium signaling dynamics to overall organ size regulation, 53 which we term the "IP3 /Ca 2+ shunt" model. This hypothesis 54 views Ca 2+ signaling as a readout of two physiological states: 55 stimulation of calcium signaling can be either growth promot-56 ing or growth inhibiti...
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