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Review
. 2022 Feb 14:10:772230.
doi: 10.3389/fcell.2022.772230. eCollection 2022.

Mechanisms Underlying Influence of Bioelectricity in Development

Laura Faith George  1 , Emily Anne Bates  1
Affiliations
Review

Mechanisms Underlying Influence of Bioelectricity in Development

Laura Faith George et al. Front Cell Dev Biol. .

Abstract

To execute the intricate process of development, cells coordinate across tissues and organs to determine where each cell divides and differentiates. This coordination requires complex communication between cells. Growing evidence suggests that bioelectrical signals controlled via ion channels contribute to cell communication during development. Ion channels collectively regulate the transmembrane potential of cells, and their function plays a conserved role in the development of organisms from flies to humans. Spontaneous calcium oscillations can be found in nearly every cell type and tissue, and disruption of these oscillations leads to defects in development. However, the mechanism by which bioelectricity regulates development is still unclear. Ion channels play essential roles in the processes of cell death, proliferation, migration, and in each of the major canonical developmental signaling pathways. Previous reviews focus on evidence for one potential mechanism by which bioelectricity affects morphogenesis, but there is evidence that supports multiple different mechanisms which are not mutually exclusive. Evidence supports bioelectricity contributing to development through multiple different mechanisms. Here, we review evidence for the importance of bioelectricity in morphogenesis and provide a comprehensive review of the evidence for several potential mechanisms by which ion channels may act in developmental processes.

Keywords: apoptosis; bioelectricity; ion channels; prolifieration; signaling; signaling pathways.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Patterns of depolarization and hyperpolarization across various developing tissues. Developing Xenopus embryos have patterns of hyperpolarization across the ectoderm during neurulation (Vandenberg et al., 2011; Adams et al., 2016). In Drosophila melanogaster, the developing wing disc at the third instar stage has a stripe of depolarized cells along the anterior posterior boundary (Emmons-Bell and Hariharan, 2021). In developing chick and mouse limbs the mesenchyme is depolarized during chondrogenic differentiation (Atsuta et al., 2019).
FIGURE 2
FIGURE 2
Roles of ion channels in cell death regulation. In the ER Reduction of calcium by blockage of SERCA or increased activity of the receptors RyR and IP3R can lead to loss of chaperone function triggering the unfolded protein response pathway, caspase activation, and ultimately cell death (A). In the mitochondria, increased levels of calcium lead to activation of the permeability transition pore (PTP) which can cause leakage of cytochrome C and ultimately cause cell death (B). Chloride and sodium both regulate cell death by regulating cell volume. Extreme imbalance of chloride or sodium levels leads to cell shrinkage or volume increase and rupture, and both cause cell death (C).
FIGURE 3
FIGURE 3
Schematic diagram of the role of ion channel function in cell cycle regulation. Ca2+/CaM regulates levels of CDK2, cyclin A, cyclin B, cyclin D, and cyclin E (A). Calcium further regulates the cell cycle through the store-operated calcium entry (SOCE) Pathway. SOCE is upregulated at the G1/S phase transition and downregulated at the G2/M phase transition (A). Potassium flux hyperpolarizes the cell, which helps drive calcium into the cell regulating calcium influence on the cell cycle (B). Chloride flux is required for the cell shrinkage that is necessary for mitosis and also regulates levels of p21 (C).
FIGURE 4
FIGURE 4
Schematic of potential mechanism by which ion channels may regulate BMP signaling. Irk2, SERCA, and Orai have all been implicated in BMP signaling, but other channels are likely involved as well. A suggested hypothesis is that these ion channels regulate depolarization events that in turn regulate the release of BMP containing vesicles. This regulated release of BMP further regulates BMP pathway activity downstream by modulating the availability of morphogen levels.
FIGURE 5
FIGURE 5
Schematic of role of ion channels in Notch signaling. The ion channels involved in regulating calcium levels in the ER including SERCA, Stim, and Orai, are required for proper localization of Notch at the cell membrane to participate in signaling. Notch signaling in turn regulates the localization and clustering of Stim. Notch signaling also attenuates the activity of potassium channels.
FIGURE 6
FIGURE 6
Schematic of mechanisms by which ion channels regulate Wnt signaling. The ER calcium regulating channels SERCA and Orai as well as potassium channels regulate the localization and trafficking of β-Catenin from the ER to the cytoplasm. This enables β-Catenin to participate in Wnt signaling.
FIGURE 7
FIGURE 7
Schematic of role of ion channel function in Hh signaling. In the Drosophila wing increased expression of Rpk and Na+/K+ ATPase and other ion channels generates a depolarized region in the developing wing disc. This depolarization is necessary for proper Smo localization and downstream stabilization of Ci. In turn, Hh signaling regulates levels of Rpk and Na+/K+ ATPase (Emmons-Bell and Hariharan, 2021).
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