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Cracking the Bioelectric Code Probing Endogenous Ionic Controls of Pattern Formation

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Cracking the Bioelectric Code Probing Endogenous Ionic Controls of Pattern Formation ARTICLE ADDENDUM ARTICLE ADDENDUM Communicative & Integrative Biology 6:1, 1–8; January/February 2013; © 2013 Landes Bioscience Cracking the bioelectric code Probing endogenous ionic controls of pattern formation AiSun Tseng† and Michael Levin* Department of Biology and Tufts Center for Regenerative and Developmental Biology; Medford, MA USA †Current affiliation: School of Life Sciences; University of Nevada-Las Vegas; Las Vegas, NV USA atterns of resting potential in non- and underlies the information process- Pexcitable cells of living tissue are ing functions required by complex pat- now known to be instructive signals for tern formation in vivo. Understanding pattern formation during embryogen- and learning to control the informa- esis, regeneration and cancer suppres- tion stored in physiological networks sion. The development of molecular-level will have transformative implications techniques for tracking ion flows and for developmental biology, regenerative functionally manipulating the activity medicine and synthetic bioengineering. of ion channels and pumps has begun to reveal the mechanisms by which volt- Introduction to Bioelectricity age gradients regulate cell behaviors and the assembly of complex large-scale It has long been known that all cells, not structures. A recent paper demonstrated just excitable nerve and muscle, drive and that a specific voltage range is necessary respond to slow changes in transmem- 1,2 for demarcation of eye fields in the frog brane potential (Vmem). Ion channels embryo. Remarkably, artificially setting and pumps segregates charges to opposite other somatic cells to the eye-specific volt- sides of plasma and organelle membranes, age range resulted in formation of eyes in producing slowly-changing differences aberrant locations, including tissues that in resting potential among cells in vivo are not in the normal anterior ectoderm (Fig. 1). Indeed spatial gradients of Vmem lineage: eyes could be formed in the gut, distributions exist also at the level of tis- on the tail, or in the lateral plate meso- sues and organs,3 and have been long- derm. These data challenge the existing known to correlate with important events models of eye fate restriction and tissue in pattern formation such as gastrula- competence maps, and suggest the pres- tion, neurogenesis and limb induction.4-7 ence of a bioelectric code—a mapping of The classical data on developmental roles physiological properties to anatomical of endogenous bioelectric signals have Keywords: bioelectricity, ion channels, outcomes. This Addendum summarizes recently been revitalized by the develop- pattern formation, regeneration the current state of knowledge in devel- ment of molecular-resolution genetic and Submitted: 08/17/12 opmental bioelectricity, proposes three pharmacological tools for the investigation Accepted: 10/19/12 possible interpretations of the bioelectric and functional control of ionic signals in code that functionally maps physiologi- vivo.8-10 Changes in resting potential regu- http://dx.doi.org/10.4161/cib.22595 cal states to anatomical outcomes, and late differentiation, proliferation, migra- *Correspondence to: Michael Levin; highlights the biggest open questions in tion and orientation11-13 of a wide variety Email: [email protected] this field. We also suggest a speculative of cell types, including stem cells, neurons hypothesis at the intersection of cogni- and neuronal precursors and migratory Addendum to: Tseng AS, Beane WS, Lemire JM, Masi A, Levin M. Induction of vertebrate tive science and developmental biology: populations such as neural crest. Recent regeneration by a transient sodium current. J that bioelectrical signaling among non- data have implicated spatiotemporal pat- Neurosci 2010; 30:13192–200; PMID: 20881138; excitable cells coupled by gap junctions terns of Vmem in the regulation of embry- DOI: 10.1523/JNEUROSCI.3315-10.2010. simulates neural network-like dynamics, onic development, regeneration and www.landesbioscience.com Communicative & Integrative Biology 1 Figure 1. Multi-scale bioelectric gradients in vivo. Segregation of ions by ion channel and pump proteins, and open high-conductivity paths (through gap junctions, cytoplasm and extracellular fluids), produce gradients of voltage potential. These exist at the level of organelles (e.g., nuclear envelope potential, A), cells (transmembrane potential, B), tissues (transepithelial potential, C) and even whole animal axes or appendages (D). Schematic drawn by Maria Lobikin. metastatic transformation.14 Thus, bio- large-scale anatomy (producing head vs. downstream effects on cells’ behavior are electric cues function alongside chemical tail) of tissues derived from the blastema induced by a given Vmem state regardless of gradients, transcriptional networks, and in regenerating flatworms.18 Importantly, whether that state was achieved by move- haptic/tensile cues as part of the morpho- these coherent changes of anatomy have ment of potassium, sodium, or chloride genetic field that orchestrates individual been analyzed to reveal the mechanistic ions,19,23,26,30,34 or of which ion transloca- cell behavior into large-scale anatomical steps leading from voltage change to cell tors’ activity resulted in the given poten- 15,16 10,29 pattern formation. behavior, revealing regulation of small tial change. Because the Vmem of cells Recent work in tractable model sys- signaling molecules’ movement through can be set by post-translational gating of tems has shown that bioelectric cues transporters as a common scheme for ion channels, pumps and gap junctions serve as mediators of positional informa- transducing bioelectrical changes into (not just at the level of gene expression), tion17 and determinants of anatomical transcriptional23,30,31 and epigenetic29,32,33 this is a true epigenetic layer of control identity during growth and morphosta- readouts. (in Waddington’s original sense of the sis.18,19 Endogenous bioelectric fields Importantly, in a number of cases, word.) The instructive signal is often mediate wound healing by coordinat- it has been shown that the patterning borne by the physiological state itself, not ing epithelial closure,20 initiate complex change produced by a specific bioelec- the genetic identity of any particular ion appendage regeneration,21,22 regulate tric signal (e.g., eye induction, neoplas- channel or pump gene. neoplastic transformation,23,24 deter- tic transformation, left-right asymmetry Thus, patterning information at the mining the left-right asymmetry of generation) is dependent only on the level of physiology regulates morphogen- internal organs,25,26 control differentia- voltage itself, not on the genetic identity esis in a number of systems. In parallel tion of mammalian adult27 and embry- of the channel or the chemical species of with the genetic and epigenetic codes, onic28 stem cells, and even dictate the the ion involved; in most cases, the same this implies the existence of a bioelectric 2 Communicative & Integrative Biology Volume 6 Issue 1 code—a quantitative mapping between wider context of the field of bioelectricity corresponding to individual organs, such ionic properties of cellular structures and molecular developmental biology? as eyes, heads, or hearts (Fig. 3A and B); and anatomical outcome. Further prog- indeed, given the fact that each cell has ress necessitates a synthesis—a concep- Major Open Questions About not one but many domains of different tual understanding of how biophysical the Bioelectric Code Vmem along its surface (Fig. 2A), the spatial properties of cells may be interpreted by distribution of voltage values could form growing tissues into specific changes of For any code, it is crucial to ask what an even richer combinatorial code and growth and form. Interestingly, recent outcomes are mapped onto which observ- store a significant amount of information data suggest three different ways by able properties of the coding medium. for a cell as well as its neighbors. Thus, which biological structures decode bio- For example, the well-established genetic it is imperative to discover whether addi- electric patterns. code maps the structure of DNA into tional voltage ranges are associated with the sequence of protein building blocks, the formation of various organ structures, but it does not directly specify morphol- and if so, whether the quantitative nature Eye Induction by Control of Vmem ogy. Precisely what aspects of pattern are of this mapping is the same across differ- The development of voltage-sensitive encoded by biophysical properties of cells? ent model systems and across individuals fluorescent dyes has facilitated the non- Three major (non-mutually-exclusive) of the same species. Note that this view invasive tracking of ionic gradients possibilities have been suggested by the focuses on one organizational level higher within single cells (Fig. 2A) and during latest data. than the prepattern model, since here the 35,36 complex pattern formation (Fig. 2B). The first is that of spatiotemporal gra- functional association of specific memV val- Moreover, strategies for targeted misex- dients of Vmem within cells and tissues as ues is with an entire complex organ, not pression of well-characterized ion trans- direct prepattern for growth and form, with direct control of transcriptional pat- locator proteins allow the investigator to an idea that was first proposed decades terns within cell fields. specifically depolarize or hyperpolarize ago.38,39 Recent studies of
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