Calcium spikes, waves and oscillations in a large, patterned epithelial tissue

Abstract

While calcium signaling in excitable cells, such as muscle or neurons, is extensively characterized, calcium signaling in epithelial tissues is little understood. Specifically, the range of intercellular calcium signaling patterns elicited by tightly coupled epithelial cells and their function in the regulation of epithelial characteristics are little explored. We found that in Drosophila imaginal discs, a widely studied epithelial model organ, complex spatiotemporal calcium dynamics occur. We describe patterns that include intercellular waves traversing large tissue domains in striking oscillatory patterns as well as spikes confined to local domains of neighboring cells. The spatiotemporal characteristics of intercellular waves and oscillations arise as emergent properties of calcium mobilization within a sheet of gap-junction coupled cells and are influenced by cell size and environmental history. While the in vivo function of spikes, waves and oscillations requires further characterization, our genetic experiments suggest that core calcium signaling components guide actomyosin organization. Our study thus suggests a possible role for calcium signaling in epithelia but importantly, introduces a model epithelium enabling the dissection of cellular mechanisms supporting the initiation, transmission and regeneration of long-range intercellular calcium waves and the emergence of oscillations in a highly coupled multicellular sheet.

Growth control in the Drosophila wing disk

“…Calcium also plays a significant, but poorly understood role in development of the wing disk. Strong phenotypes, including blistered or bent wings, result when Ca 2+ signaling is perturbed (Balaji et al, ; Brodskiy et al, ; Dahal et al, ; Dahal, Pradhan, & Bates, ). Ca 2+ is a second messenger, and Ca 2+ signaling networks often exhibit a “bow‐tie” structure in that the integrated effect of many inputs is governed by a small number of molecules in the calcium pathway, and they affect many outputs (Brodskiy & Zartman, ), similar to the way that many growth‐affecting factors impinge upon the Hippo kinase cascade.…”

“…Ca 2+ is a second messenger, and Ca 2+ signaling networks often exhibit a “bow‐tie” structure in that the integrated effect of many inputs is governed by a small number of molecules in the calcium pathway, and they affect many outputs (Brodskiy & Zartman, ), similar to the way that many growth‐affecting factors impinge upon the Hippo kinase cascade. Like Hippo, growth and mechanical signals both affect Ca 2+ (Antunes, Pereira, Cordeiro, Almeida, & Jacinto, ; Balaji et al, ; Brodskiy et al, ; Narciso et al, ; Narciso, Contento, Storey, Hoelzle, & Zartman, ; Restrepo & Basler, ). Ca 2+ signaling in the wing disk exhibits a rich variety of dynamical behaviors.…”

Spatiotemporal dynamics of calcium transients during embryogenesis of Drosophila melanogaster

“…It is unlikely that the establishment of gap junctions is involved in this time window, as calcium waves could already be experimentally induced several hours earlier (Hunter et al 2014). In Drosophila, soluble extract of wing disc triggers calcium epithelial waves (Balaji et al 2017) and morphogen regulates their amplitude and frequency (Wu, Brodskiy, Huizar, et al 2017). It is possible that the secretion of a specific molecular component controls the embryonic calcium waves described here.…”

Interplay between morphogen‐directed positional information systems and physiological signaling

“…A potential explanation for similar outcomes in Dpp and Ca 2+ after Irk channel inhibition is that intracellular Ca 2+ dynamics regulate Dpp release, although whether or not Ca 2+ has a causative effect requires further study. Several studies have shown that Ca 2+ is crucial to regulation of epithelial physiology during development . However, whether Ca 2+ directly regulates Dpp secretion is currently unknown.…”

“…Several studies have shown that Ca 2+ is crucial to regulation of epithelial physiology during development. [45][46][47][48][49][50] However, whether Ca 2+ directly regulates Dpp secretion is currently unknown. Given that misregulation of Ca 2+ is frequently associated with developmental genetic disorders resulting in neoplasms, 51 it is necessary to further characterize the roles of Ca 2+ and other second messengers in morphogen transport and morphogenesis to provide insight into therapies to treat these genetic disorders.…”