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

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 dis...

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Autores principales:	Dharsan K. Soundarrajan, Francisco J. Huizar, Ramezan Paravitorghabeh, Trent Robinett, Jeremiah J. Zartman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/babe929a72df4c3298b7cbd7e4786b86
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spelling	oai:doaj.org-article:babe929a72df4c3298b7cbd7e4786b862021-11-25T05:42:05ZFrom spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control1553-734X1553-7358https://doaj.org/article/babe929a72df4c3298b7cbd7e4786b862021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601605/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Information 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. Author summary Calcium (Ca2+) is a universal second messenger that regulates a myriad of cellular processes such as cell division, cell proliferation and apoptosis. Multiple patterns of Ca2+ signaling including single-cell spikes, multicellular Ca2+ transients, large-scale Ca2+ waves, and global “fluttering” have been observed in epithelial systems during organ development. Key molecular players and biophysical mechanisms involved in formation of these patterns during organ development are not well understood. In this work, we developed a generalized multicellular model of Ca2+ that captures all the key categories of Ca2+ activity as a function of key hormonal signals. Integration of model predictions and experiments reveals two subclasses of cell populations and demonstrates that Ca2+ signaling activity at the organ scale is defined by a general decrease in gap junction communication as an organ grows. Our experiments also reveal that a “goldilocks zone” of optimal Ca2+ activity is required to achieve optimal growth at the organ level.Dharsan K. SoundarrajanFrancisco J. HuizarRamezan ParavitorghabehTrent RobinettJeremiah J. ZartmanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Dharsan K. Soundarrajan Francisco J. Huizar Ramezan Paravitorghabeh Trent Robinett Jeremiah J. Zartman From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
description	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. Author summary Calcium (Ca2+) is a universal second messenger that regulates a myriad of cellular processes such as cell division, cell proliferation and apoptosis. Multiple patterns of Ca2+ signaling including single-cell spikes, multicellular Ca2+ transients, large-scale Ca2+ waves, and global “fluttering” have been observed in epithelial systems during organ development. Key molecular players and biophysical mechanisms involved in formation of these patterns during organ development are not well understood. In this work, we developed a generalized multicellular model of Ca2+ that captures all the key categories of Ca2+ activity as a function of key hormonal signals. Integration of model predictions and experiments reveals two subclasses of cell populations and demonstrates that Ca2+ signaling activity at the organ scale is defined by a general decrease in gap junction communication as an organ grows. Our experiments also reveal that a “goldilocks zone” of optimal Ca2+ activity is required to achieve optimal growth at the organ level.
format	article
author	Dharsan K. Soundarrajan Francisco J. Huizar Ramezan Paravitorghabeh Trent Robinett Jeremiah J. Zartman
author_facet	Dharsan K. Soundarrajan Francisco J. Huizar Ramezan Paravitorghabeh Trent Robinett Jeremiah J. Zartman
author_sort	Dharsan K. Soundarrajan
title	From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
title_short	From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
title_full	From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
title_fullStr	From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
title_full_unstemmed	From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control
title_sort	from spikes to intercellular waves: tuning intercellular calcium signaling dynamics modulates organ size control
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/babe929a72df4c3298b7cbd7e4786b86
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From spikes to intercellular waves: Tuning intercellular calcium signaling dynamics modulates organ size control

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