Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation

Abstract

Alongside the well-known chemical modes of cell-cell communication, we find an important and powerful system of bioelectrical signaling: changes in the resting voltage potential (Vmem) of the plasma membrane driven by ion channels, pumps and gap junctions. Slow Vmem changes in all cells serve as a highly conserved, information-bearing pathway that regulates cell proliferation, migration and differentiation. In embryonic and regenerative pattern formation and in the disorganization of neoplasia, bioelectrical cues serve as mediators of large-scale anatomical polarity, organ identity and positional information. Recent developments have resulted in tools that enable a high-resolution analysis of these biophysical signals and their linkage with upstream and downstream canonical genetic pathways. Here, we provide an overview for the study of bioelectric signaling, focusing on state-of-the-art approaches that use molecular physiology and developmental genetics to probe the roles of bioelectric events functionally. We highlight the logic, strategies and well-developed technologies that any group of researchers can employ to identify and dissect ionic signaling components in their own work and thus to help crack the bioelectric code. The dissection of bioelectric events as instructive signals enabling the orchestration of cell behaviors into large-scale coherent patterning programs will enrich on-going work in diverse areas of biology, as biophysical factors become incorporated into our systems-level understanding of cell interactions.

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS

“…1A). As previously documented by us and others, we saw no sign of general toxicity or non-specific ill health [midline patterning, scale, proportions and overall growth were normal; (Adams and Levin, 2013, Blackiston et al, 2011, Pai et al, 2012a (Pai et al, 2015, Pai et al, 2012a]. Uninjected and water-injected embryos served as controls.…”

“…Dynamic changes in resting membrane potentials (V mem ) carry patterning information during embryonic organ development in Xenopus (Adams and Levin, 2013, Levin, 2014a, Mustard and Levin, 2014, Tseng and Levin, 2013b, Vandenberg et al, 2011. In addition to activity-dependent sculpting of neural connections (Kozorovitskiy et al, 2012, Penn andShatz, 1999), the spatial distribution patterns of V mem in developing embryos controls aspects of large-scale morphogenesis of the nervous system, particularly eye and brain (Beane et al, 2013, Pai et al, 2015, Pai et al, 2012a, Pai et al, 2012b.…”

Selective depolarization of transmembrane potential alters muscle patterning and muscle cell localization in Xenopus laevis embryos

“…To confirm this, we reproduced the same phenotype using sodium flux -a strategy often used to interrogate bioelectric signaling (Adams and Levin, 2013). TPC3 is a newly identified two-pore channel, selective for sodium ions, that has an activity profile similar to that of native Na v channels when injected into Xenopus oocytes (Cang et al, 2014).…”

Cell-to-cell communication: current views and future perspectives

“…Several examples from the literature are included in this broad and well-structured review illustrating the deep involvement of mechanical forces in fundamental cell-to-cell communication pathways. In the last contribution of the first part, Adams and Levin (2012) introduce the fascinating field of bioelectrical signalling elicited by ion-channel-dependent changes in the resting potential of the plasma membrane of cells. The authors explain how, in embryonic and regenerative pattern formation, bioelectrical cues serve as mediators, e.g., of positional information and large-scale anatomical polarity.…”