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

Soundarrajan, Dharsan K.; Huizar, Francisco J.; Paravitorghabeh, Ramezan; Robinett, Trent; Zartman, Jeremiah J.

doi:10.1371/journal.pcbi.1009543

Cited by 11 publications

(24 citation statements)

References 78 publications

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“…Studies in Drosophila demonstrated intercellular Ca 2+ waves that traverse large tissue domains and might depend on actomyosin organization ( Balaji et al, 2017 ). These tissue-level Ca 2+ dynamics, which occur in imaginal discs, the tightly coupled epithelial structures that give rise to the external structures of the adult fly, were implicated in organ growth and size modulation ( Brodskiy et al, 2019 ; Soundarrajan et al, 2021 preprint). Furthermore, intercellular Ca 2+ waves were shown to be induced mechanically in these developing epithelia ( Narciso et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ

Kim

Nguyen

Marchetti

et al. 2022

Journal of Cell Science

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Cytosolic calcium is a highly dynamic, tightly regulated, and broadly conserved cellular signal. Calcium dynamics have been studied widely in cellular monocultures, yet organs in vivo comprise heterogeneous populations of stem and differentiated cells. Here we examine calcium dynamics in the adult Drosophila intestine, a self-renewing epithelial organ in which stem cells continuously produce daughters that differentiate into either enteroendocrine cells or enterocytes. Live imaging of whole organs ex vivo reveals that stem cell daughters adopt strikingly distinct patterns of calcium oscillations after differentiation: Enteroendocrine cells exhibit single-cell calcium oscillations, while enterocytes exhibit rhythmic, long-range calcium waves. These multicellular waves do not propagate through immature progenitors (stem cells and enteroblasts), whose oscillation frequency is approximately half that of enteroendocrine cells. Organ-scale inhibition of gap junctions eliminates calcium oscillations in all cell types--even, intriguingly, in progenitor and enteroendocrine cells that are surrounded only by enterocytes. Our findings establish that cells adopt fate-specific modes of calcium dynamics as they terminally differentiate and reveal that the oscillatory dynamics of different cell types in a single, coherent epithelium are paced independently.

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Section: Introductionmentioning

confidence: 99%

Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ

Kim

Nguyen

Marchetti

et al. 2022

Journal of Cell Science

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“…Additionally, their model is implemented over a two-dimensional, homogenized continuum rather than over discrete cells in a tissue. A more recent model from the same lab investigates calcium signaling across a Drosophila wing disc, but with a focus on organ development and with the total IP 3 production rate in each cell being just a function of the cytosolic calcium concentration (Soundarrajan et al ., 2021). Donati et al (2021) developed a model of calcium signals in mouse keratinocytes upon photodamage; however, instead of proteolytic activation driving the extracellular signaling mechanism, the damage signal in that system is ATP, which is released both from the wound site as well as from undamaged cells through connexin hemichannels.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A mathematical model of calcium signals around laser-induced epithelial wounds

Stevens

O’Connor

Pumford

et al. 2022

Preprint

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Cells around epithelial wounds must first become aware of the wound in order to initiate the wound healing process. An initial response to an epithelial wound is an increase in cytosolic calcium followed by complex calcium signaling events. While these calcium signals are driven by both physical and chemical wound responses, cells around the wound will all be equipped with the same cellular components to produce and interact with the calcium signals. Here, we have developed a mathematical model in the context of laser-ablation of the Drosophila pupal notum that integrates tissue-level damage models with a cellular calcium signaling toolkit. The model replicates experiments in the contexts of control wounds as well as knockdowns of specific cellular components, but it also provides new insights that are not easily accessible experimentally. The model suggests that cell-cell variability is necessary to produce calcium signaling events observed in experiments, it quantifies calcium concentrations during wound-induced signaling events, and it shows that intercellular transfer of the molecule IP3 is required to coordinate calcium signals across distal cells around the wound. The mathematical model developed here serves as a framework for quantitative studies in both wound signaling and calcium signaling in the Drosophila system.

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“…The copyright holder for this preprint this version posted January 9, 2023. ; https://doi.org/10.1101/2023.01.08.523049 doi: bioRxiv preprint Previously, we have shown that perturbing Gαq expression regulates the size of Drosophila wings [46]. Further, we identified that the overexpression of wildtype Gαq is correlated with the occurrence of intercellular Ca 2+ waves (ICWs) in ex vivo wing disc cultures [46]. Further, Gαq is required for wound-induced Ca 2+ waves in the pupal notum [47], [48].…”

Section: Introductionmentioning

confidence: 99%

The multimodal action of G alpha q in coordinating growth and homeostasis in theDrosophilawing imaginal disc

Velagala

Soundarrajan

Unger

et al. 2023

Preprint

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Background: G proteins mediate cell responses to various ligands and play key roles in organ development. Dysregulation of G-proteins or Ca2+ signaling impacts many human diseases and results in birth defects. However, the downstream effectors of specific G proteins in developmental regulatory networks are still poorly understood. Methods: We employed the Gal4/UAS binary system to inhibit or overexpress Gαq in the wing disc, followed by phenotypic analysis. Immunohistochemistry and next-gen RNA sequencing identified the downstream effectors and the signaling cascades affected by the disruption of Gαq homeostasis. Results: Here, we characterized how the G protein subunit Gαq tunes the size and shape of the wing in the larval and adult stages of development. Downregulation of Gαq in the wing disc reduced wing growth and delayed larval development. Gαq overexpression is sufficient to promote global Ca2+ waves in the wing disc with a concomitant reduction in the Drosophila final wing size and a delay in pupariation. The reduced wing size phenotype is further enhanced when downregulating downstream components of the core Ca2+ signaling toolkit, suggesting that downstream Ca2+ signaling partially ameliorates the reduction in wing size. In contrast, Gαq-mediated pupariation delay is rescued by inhibition of IP3R, a key regulator of Ca2+ signaling. This suggests that Gαq regulates developmental phenotypes through both Ca2+-dependent and Ca2+-independent mechanisms. RNA seq analysis shows that disruption of Gαq homeostasis affects nuclear hormone receptors, JAK/STAT pathway, and immune response genes. Notably, disruption of Gαq homeostasis increases expression levels of Dilp8, a key regulator of growth and pupariation timing. Conclusion: Gαq activity contributes to cell size regulation and wing metamorphosis. Disruption to Gαq homeostasis in the peripheral wing disc organ delays larval development through ecdysone signaling inhibition. Overall, Gαq signaling mediates key modules of organ size regulation and epithelial homeostasis through the dual action of Ca2+-dependent and independent mechanisms.

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

Cited by 11 publications

References 78 publications

Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ

Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ

A mathematical model of calcium signals around laser-induced epithelial wounds

The multimodal action of G alpha q in coordinating growth and homeostasis in theDrosophilawing imaginal disc

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