Developmental bioelectricity explained

Developmental bioelectricity is the regulation of cell, tissue, and organ-level patterning and behavior by electrical signals during the development of embryonic animals and plants. The charge carrier in developmental bioelectricity is the ion (a charged atom) rather than the electron, and an electric current and field is generated whenever a net ion flux occurs. Cells and tissues of all types use flows of ions to communicate electrically. Endogenous electric currents and fields, ion fluxes, and differences in resting potential across tissues comprise a signalling system. It functions along with biochemical factors, transcriptional networks, and other physical forces to regulate cell behaviour and large-scale patterning in processes such as embryogenesis, regeneration, and cancer suppression.

Overview

Developmental bioelectricity is a sub-discipline of biology, related to, but distinct from, neurophysiology and bioelectromagnetics. Developmental bioelectricity refers to the endogenous ion fluxes, transmembrane and transepithelial voltage gradients, and electric currents and fields produced and sustained in living cells and tissues.[1] [2] This electrical activity is often used during embryogenesis, regeneration, and cancer suppression—it is one layer of the complex field of signals that impinge upon all cells in vivo and regulate their interactions during pattern formation and maintenance. This is distinct from neural bioelectricity (classically termed electrophysiology), which refers to the rapid and transient spiking in well-recognized excitable cells like neurons and myocytes (muscle cells);[3] and from bioelectromagnetics, which refers to the effects of applied electromagnetic radiation, and endogenous electromagnetics such as biophoton emission and magnetite.[4] [5]

The inside/outside discontinuity at the cell surface enabled by a lipid bilayer membrane (capacitor) is at the core of bioelectricity. The plasma membrane was an indispensable structure for the origin and evolution of life itself. It provided compartmentalization permitting the setting of a differential voltage/potential gradient (battery or voltage source) across the membrane, probably allowing early and rudimentary bioenergetics that fueled cell mechanisms.[6] [7] During evolution, the initially purely passive diffusion of ions (charge carriers), become gradually controlled by the acquisition of ion channels, pumps, exchangers, and transporters. These energetically free (resistors or conductors, passive transport) or expensive (current sources, active transport) translocators set and fine tune voltage gradients – resting potentials – that are ubiquitous and essential to life's physiology, ranging from bioenergetics, motion, sensing, nutrient transport, toxins clearance, and signaling in homeostatic and disease/injury conditions. Upon stimuli or barrier breaking (short-circuit) of the membrane, ions powered by the voltage gradient (electromotive force) diffuse or leak, respectively, through the cytoplasm and interstitial fluids (conductors), generating measurable electric currents – net ion fluxes – and fields. Some ions (such as calcium) and molecules (such as hydrogen peroxide) modulate targeted translocators to produce a current or to enhance, mitigate or even reverse an initial current, being switchers.[8] [9]

Endogenous bioelectric signals are produced in cells by the cumulative action of ion channels, pumps, and transporters. In non-excitable cells, the resting potential across the plasma membrane (Vmem) of individual cells propagate across distances via electrical synapses known as gap junctions (conductors), which allow cells to share their resting potential with neighbors. Aligned and stacked cells (such as in epithelia) generate transepithelial potentials (such as batteries in series) and electric fields, which likewise propagate across tissues.[10] Tight junctions (resistors) efficiently mitigate the paracellular ion diffusion and leakage, precluding the voltage short circuit. Together, these voltages and electric fields form rich and dynamic and patterns inside living bodies that demarcate anatomical features, thus acting like blueprints for gene expression and morphogenesis in some instances. More than correlations, these bioelectrical distributions are dynamic, evolving with time and with the microenvironment and even long-distant conditions to serve as instructive influences over cell behavior and large-scale patterning during embryogenesis, regeneration, and cancer suppression.[2] [11] [12] [13] Bioelectric control mechanisms are an important emerging target for advances in regenerative medicine, birth defects, cancer, and synthetic bioengineering.[14] [15]

History

18th century

Developmental bioelectricity began in the 18th century. Several seminal works stimulating muscle contractions using Leyden jars culminated with the publication of classical studies by Luigi Galvani in 1791 (De viribus electricitatis in motu musculari) and 1794. In these, Galvani thought to have uncovered intrinsic electric-producing ability in living tissues or "animal electricity". Alessandro Volta showed that the frog's leg muscle twitching was due to a static electricity generator and from dissimilar metals undergoing or catalyzing electrochemical reactions. Galvani showed, in a 1794 study, twitching without metal electricity by touching the leg muscle with a deviating cut sciatic nerve, definitively demonstrating "animal electricity".[16] [17] [18] Unknowingly, Galvani with this and related experiments discovered the injury current (ion leakage driven by the intact membrane/epithelial potential) and injury potential (potential difference between injured and intact membrane/epithelium). The injury potential was, in fact, the electrical source behind the leg contraction, as realized in the next century.[19] [20] Subsequent work ultimately extended this field broadly beyond nerve and muscle to all cells, from bacteria to non-excitable mammalian cells.

19th century

Building on earlier studies, further glimpses of developmental bioelectricity occurred with the discovery of wound-related electric currents and fields in the 1840s, when the electrophysiologist Emil du Bois-Reymond reported macroscopic level electrical activities in frog, fish and human bodies. He recorded minute electric currents in live tissues and organisms with a then state-of-the-art galvanometer made of insulated copper wire coils. He unveiled the fast-changing electricity associated with muscle contraction and nerve excitation – the action potentials.[21] [22] [23] Du Bois-Reymond also reported in detail less fluctuating electricity at wounds – injury current and potential – he made to himself.[24] [25]

Early 20th century

Developmental bioelectricity work began in earnest at the beginning of the 20th century.[26] Ida H. Hyde studied the role of electricity in the development of eggs.[27] T. H. Morgan and others studied the electrophysiology of the earthworm.[28] Oren E. Frazee studied the effects of electricity on limb regeneration in amphibians.[29] E. J. Lund explored morphogenesis in flowering plants.[30] Libbie Hyman studied vertebrate and invertebrate animals.[31] [32]

In the 1920s and 1930s, Elmer J. Lund[33] and Harold Saxton Burr[34] wrote multiple papers about the role of electricity in embryonic development. Lund measured currents in a large number of living model systems, correlating them to changes in patterning. In contrast, Burr used a voltmeter to measure voltage gradients, examining developing embryonic tissues and tumors, in a range of animals and plants. Applied electric fields were demonstrated to alter the regeneration of planarian by Marsh and Beams in the 1940s and 1950s,[35] [36] inducing the formation of heads or tails at cut sites, reversing the primary body polarity.

Late 20th century

In the 1970s, Lionel Jaffe and Richard Nuccittelli's introduction and development of the vibrating probe, the first device for quantitative non-invasive characterization of the extracellular minute ion currents, revitalized the field.[37] [38] [39] [40] [41] Researchers such as Joseph Vanable, Richard Borgens, Ken Robinson, and Colin McCaig explored the roles of endogenous bioelectric signaling in limb development and regeneration, embryogenesis, organ polarity, and wound healing.[42] [43] [20] [44]

C.D. Cone studied the role of resting potential in regulating cell differentiation and proliferation.[45] [46] Subsequent work has identified specific regions of the resting potential spectrum that correspond to distinct cell states such as quiescent, stem, cancer, and terminally differentiated.[47]

Although this body of work generated a significant amount of high-quality physiological data, this large-scale biophysics approach has historically come second to the study of biochemical gradients and genetic networks in biology education, funding, and overall popularity among biologists. A key factor that contributed to this field lagging behind molecular genetics and biochemistry is that bioelectricity is inherently a living phenomenon – it cannot be studied in fixed specimens. Working with bioelectricity is more complex than traditional approaches to developmental biology, both methodologically and conceptually, as it typically requires a highly interdisciplinary approach.[12]

Study techniques

Electrodes

The gold standard techniques to quantitatively extract electric dimensions from living specimens, ranging from cell to organism levels, are the glass microelectrode (or micropipette), the vibrating (or self-referencing) voltage probe, and the vibrating ion-selective microelectrode. The former is inherently invasive, and the two latter are non-invasive, but all are ultra-sensitive[48] and fast-responsive sensors extensively used in a plethora of physiological conditions in widespread biological models.[49] [50] [8] [51] [20]

The glass microelectrode was developed in the 1940s to study the action potential of excitable cells, deriving from the seminal work by Hodgkin and Huxley in the giant axon squid.[52] [53] It is simply a liquid salt bridge connecting the biological specimen with the electrode, protecting tissues from leachable toxins and redox reactions of the bare electrode. Owing to its low impedance, low junction potential and weak polarization, silver electrodes are standard transducers of the ionic into electric current that occurs through a reversible redox reaction at the electrode surface.[54]

The vibrating probe was introduced in biological studies in the 1970s.[55] [56] [37] The voltage-sensitive probe is electroplated with platinum to form a capacitive black tip ball with large surface area. When vibrating in an artificial or natural DC voltage gradient, the capacitive ball oscillates in a sinusoidal AC output. The amplitude of the wave is proportional to the measuring potential difference at the frequency of the vibration, efficiently filtered by a lock-in amplifier that boosts probe's sensitivity.[37] [57] [58]

The vibrating ion-selective microelectrode was first used in 1990 to measure calcium fluxes in various cells and tissues.[59] The ion-selective microelectrode is an adaptation of the glass microelectrode, where an ion-specific liquid ion exchanger (ionophore) is tip-filled into a previously silanized (to prevent leakage) microelectrode. Also, the microelectrode vibrates at low frequencies to operate in the accurate self-referencing mode. Only the specific ion permeates the ionophore, therefore the voltage readout is proportional to the ion concentration in the measuring condition. Then, flux is calculated using the Fick's first law.[57] [60]

Emerging optic-based techniques,[61] for example, the pH optrode (or optode), which can be integrated into a self-referencing system may become an alternative or additional technique in bioelectricity laboratories. The optrode does not require referencing and is insensitive to electromagnetism[62] simplifying system setting up and making it a suitable option for recordings where electric stimulation is simultaneously applied.

Much work to functionally study bioelectric signaling has made use of applied (exogenous) electric currents and fields via DC and AC voltage-delivering apparatus integrated with agarose salt bridges.[63] These devices can generate countless combinations of voltage magnitude and direction, pulses, and frequencies. Currently, lab-on-a-chip mediated application of electric fields is gaining ground in the field with the possibility to allow high-throughput screening assays of the large combinatory outputs.[64]

Fluorescence

Progress in molecular biology over the last six decades has produced powerful tools that facilitate the dissection of biochemical and genetic signals; yet, they tend to not be well-suited for bioelectric studies in vivo. Prior work relied extensively on current applied directly by electrodes, reinvigorated by significant recent advances in materials science[65] [66] [67] [68] [69] [70] and extracellular current measurements, facilitated by sophisticated self-referencing electrode systems.[71] [72] While electrode applications for manipulating neuraly-controlled body processes have recently attracted much attention,[73] [74] there are other opportunities for controlling somatic processes, as most cell types are electrically active and respond to ionic signals from themselves and their neighbors.

In the early part of the 21st century, a number of new molecular techniques were developed that allowed bioelectric pathways to be investigated with a high degree of mechanistic resolution, and to be linked to canonical molecular cascades.[75] These include:

  1. Pharmacological screens to identify endogenous channels and pumps responsible for specific patterning events;[76] [77] [78]
  2. Voltage-sensitive fluorescent reporter dyes and genetically encoded fluorescent voltage indicators for the characterization of the bioelectric state in vivo.[79] [80] [81] [82] [83]
  3. Panels of well-characterized dominant ion channels that can be misexpressed in cells of interest to alter the bioelectric state in desired ways;[78] [84] [85] and
  4. Computational platforms that are coming on-line[86] [87] to assist in building predictive models of bioelectric dynamics in tissues.[88] [89] [90]

Compared with the electrode-based techniques, the molecular probes provide a wider spatial resolution and facilitated dynamic analysis over time. Although calibration or titration can be possible, molecular probes are typically semi-quantitative, whereas electrodes provide absolute bioelectric values. Another advantage of fluorescence and other probes is their less-invasive nature and spatial multiplexing, enabling the simultaneous monitoring of large areas of embryonic or other tissues in vivo during normal or pathological pattering processes.[91]

Roles in organisms

Early development

Work in model systems such as Xenopus laevis and zebrafish has revealed a role for bioelectric signaling in the development of heart,[92] [93] face,[94] [95] eye,[84] brain,[96] [97] and other organs. Screens have identified roles for ion channels in size control of structures such as the zebrafish fin,[98] while focused gain-of-function studies have shown for example that body parts can be re-specified at the organ level – for example creating entire eyes in gut endoderm.[84] As in the brain, developmental bioelectrics can integrate information across significant distance in the embryo, for example such as the control of brain size by bioelectric states of ventral tissue.[97] and the control of tumorigenesis at the site of oncogene expression by bioelectric state of remote cells.[99] [100]

Human disorders, as well as numerous mouse mutants show that bioelectric signaling is important for human development (Tables 1 and 2). Those effects are pervasively linked to channelopathies, which are human disorders that result from mutations that disrupt ion channels.

Several channelopathies result in morphological abnormalities or congenital birth defects in addition to symptoms that affect muscle and or neurons. For example, mutations that disrupt an inwardly rectifying potassium channel Kir2.1 cause dominantly inherited Andersen-Tawil Syndrome (ATS). ATS patients experience periodic paralysis, cardiac arrhythmias, and multiple morphological abnormalities that can include cleft or high arched palate, cleft or thin upper lip, flattened philtrum, micrognathia, dental oligodontia, enamel hypoplasia, delayed dentition eruption, malocclusion, broad forehead, wide set eyes, low set ears, syndactyly, clinodactyly, brachydactyly, and dysplastic kidneys.[101] [102] Mutations that disrupt another inwardly rectifying K+ channel Girk2 encoded by KCNJ6 cause Keppen-Lubinsky syndrome which includes microcephaly, a narrow nasal bridge, a high arched palate, and severe generalized lipodystrophy (failure to generate adipose tissue).[103] KCNJ6 is in the Down syndrome critical region such that duplications that include this region lead to craniofacial and limb abnormalities and duplications that do not include this region do not lead to morphological symptoms of Down syndrome.[104] [105] [106] [107] Mutations in KCNH1, a voltage gated potassium channel lead to Temple-Baraitser (also known as Zimmermann- Laband) syndrome. Common features of Temple-Baraitser syndrome include absent or hypoplastic of finger and toe nails and phalanges and joint instability. Craniofacial defects associated with mutations in KCNH1 include cleft or high arched palate, hypertelorism, dysmorphic ears, dysmorphic nose, gingival hypertrophy, and abnormal number of teeth.[108] [109] [110] [111] [112] [113] [114]

Mutations in CaV1.2, a voltage gated Ca2+ channel, lead to Timothy syndrome, which causes severe cardiac arrhythmia (long-QT) along with syndactyly and similar craniofacial defects to Andersen-Tawil syndrome including cleft or high-arched palate, micrognathia, low set ears, syndactyly and brachydactyly.[115] [116] While these channelopathies are rare, they show that functional ion channels are important for development. Furthermore, in utero exposure to anti-epileptic medications that target some ion channels also cause increased incidence of birth defects such as oral cleft.[117] [118] [119] [120] [121] The effects of both genetic and exogenous disruption of ion channels lend insight into the importance of bioelectric signaling in development.

Wound healing and cell guidance

One of the best-understood roles for bioelectric gradients is at the tissue-level endogenous electric fields utilized during wound healing. It is challenging to study wound-associated electric fields, because these fields are weak, less fluctuating, and do not have immediate biological responses when compared to nerve pulses and muscle contraction. The development of the vibrating and glass microelectrodes, demonstrated that wounds indeed produced and, importantly, sustained measurable electric currents and electric fields.[37] [122] [56] [123] [124] [125] These techniques allow further characterization of the wound electric fields/currents at cornea and skin wounds, which show active spatial and temporal features, suggesting active regulation of these electrical phenomena. For example, the wound electric currents are always the strongest at the wound edge, which gradually increased to reach a peak about 1 hour after injury.[126] [127] [58] At wounds in diabetic animals, the wound electric fields are significantly compromised.[128] Understanding the mechanisms of generation and regulation of the wound electric currents/fields is expected to reveal new approaches to manipulate the electrical aspect for better wound healing.

How are the electric fields at a wound produced? Epithelia actively pump and differentially segregate ions. In the cornea epithelium, for example, Na+ and K+ are transported inwards from tear fluid to extracellular fluid, and Cl− is transported out of the extracellular fluid into the tear fluid. The epithelial cells are connected by tight junctions, forming the major electrical resistive barrier, and thus establishing an electrical gradient across the epithelium – the transepithelial potential (TEP).[129] [130] Breaking the epithelial barrier, as occurs in any wounds, creates a hole that breaches the high electrical resistance established by the tight junctions in the epithelial sheet, short-circuiting the epithelium locally. The TEP therefore drops to zero at the wound. However, normal ion transport continues in unwounded epithelial cells beyond the wound edge (typically <1 mm away), driving positive charge flow out of the wound and establishing a steady, laterally-oriented electric field (EF) with the cathode at the wound. Skin also generates a TEP, and when a skin wound is made, similar wound electric currents and fields arise, until the epithelial barrier function recovers to terminate the short-circuit at the wound. When wound electric fields are manipulated with pharmacological agents that either stimulate or inhibit transport of ions, the wound electric fields also increase or decrease, respectively. Wound healing can be speed up or slowed down accordingly in cornea wounds.[126] [127] [131]

How do electric fields affect wound healing? To heal wounds, cells surrounding the wound must migrate and grow directionally into the wound to cover the defect and restore the barrier. Cells important to heal wounds respond remarkably well to applied electric fields of the same strength that are measured at wounds. The whole gamut of cell types and their responses following injury are affected by physiological electric fields. Those include migration and division of epithelial cells, sprouting and extension of nerves, and migration of leukocytes and endothelial cells.[132] [133] [134] [135] The most well studied cellular behavior is directional migration of epithelial cells in electric fields – electrotaxis. The epithelial cells migrate directionally to the negative pole (cathode), which at a wound is the field polarity of the endogenous vectorial electric fields in the epithelium, pointing (positive to negative) to the wound center. Epithelial cells of the cornea, keratinocytes from the skin, and many other types of cells show directional migration at electric field strengths as low as a few mV mm−1.[136] [137] [138] [139] Large sheets of monolayer epithelial cells, and sheets of stratified multilayered epithelial cells also migrate directionally.[127] [140] Such collective movement closely resembles what happens during wound healing in vivo, where cell sheets move collectively into the wound bed to cover the wound and restore the barrier function of the skin or cornea.

How cells sense such minute extracellular electric fields remains largely elusive. Recent research has started to identify some genetic, signaling and structural elements underlying how cells sense and respond to small physiological electric fields. These include ion channels, intracellular signaling pathways, membrane lipid rafts, and electrophoresis of cellular membrane components.[141] [142] [143] [144] [145] [146] [147]

Limb regeneration in animals

In the early 20th century, Albert Mathews seminally correlated regeneration of a cnidarian polyp with the potential difference between polyp and stolon surfaces, and affected regeneration by imposing countercurrents. Amedeo Herlitzka, following on the wound electric currents footsteps of his mentor, du Bois-Raymond, theorized about electric currents playing an early role in regeneration, maybe initiating cell proliferation.[148] Using electric fields overriding endogenous ones, Marsh and Beams astoundingly generated double-headed planarians and even reversed the primary body polarity entirely, with tails growing where a head previously existed.[149] After these seed studies, variations of the idea that bioelectricity could sense injury and trigger or at least be a major player in regeneration have spurred over the decades until the present day. A potential explanation lies on resting potentials (primarily Vmem and TEP), which can be, at least in part, dormant sensors (alarms) ready to detect and effectors (triggers) ready to react to local damage.[122] [150] [151] [9]

Following up on the relative success of electric stimulation on non-permissive frog leg regeneration using an implanted bimetallic rod in the late 1960s,[152] the bioelectric extracellular aspect of amphibian limb regeneration was extensively dissected in the next decades. Definitive descriptive and functional physiological data was made possible owing to the development of the ultra-sensitive vibrating probe and improved application devices.[37] [153] Amputation invariably leads to a skin-driven outward current and a consequent lateral electric field setting the cathode at the wound site. Although initially pure ion leakage, an active component eventually takes place and blocking ion translocators typically impairs regeneration. Using biomimetic exogenous electric currents and fields, partial regeneration was achieved, which typically included tissue growth and increased neuronal tissue. Conversely, precluding or reverting endogenous electric current and fields impairs regeneration.[56] [154] [153] [155] These studies in amphibian limb regeneration and related studies in lampreys and mammals [156] combined with those of bone fracture healing[157] [158] and in vitro studies,[127] led to the general rule that migrating (such as keratinocytes, leucocytes and endothelial cells) and outgrowing (such as axons) cells contributing to regeneration undergo electrotaxis towards the cathode (injury original site). Congruently, an anode is associated with tissue resorption or degeneration, as occurs in impaired regeneration and osteoclastic resorption in bone.[157] [155] [159] Despite these efforts, the promise for a significant epimorphic regeneration in mammals remains a major frontier for future efforts, which includes the use of wearable bioreactors to provide an environment within which pro-regenerative bioelectric states can be driven[160] [161] and continued efforts at electrical stimulation.[162]

Recent molecular work has identified proton and sodium flux as being important for tail regeneration in Xenopus tadpoles,[9] [163] [164] and shown that regeneration of the entire tail (with spinal cord, muscle, etc.) could be triggered in a range of normally non-regenerative conditions by either molecular-genetic,[165] pharmacological,[166] or optogenetic[167] methods. In planaria, work on bioelectric mechanism has revealed control of stem cell behavior,[168] size control during remodeling,[169] anterior-posterior polarity,[170] and head shape.[171] Gap junction-mediated alteration of physiological signaling produces two-headed worms in Dugesia japonica; remarkably, these animals continue to regenerate as two-headed in future rounds of regeneration months after the gap junction-blocking reagent has left the tissue.[172] [173] [174] This stable, long-term alteration of the anatomical layout to which animals regenerate, without genomic editing, is an example of epigenetic inheritance of body pattern, and is also the only available "strain" of planarian species exhibiting an inherited anatomical change that is different from the wild-type.[175]

Cancer

Defection of cells from the normally tight coordination of activity towards an anatomical structure results in cancer; it is thus no surprise that bioelectricity – a key mechanism for coordinating cell growth and patterning – is a target often implicated in cancer and metastasis.[176] [177] Indeed, it has long been known that gap junctions have a key role in carcinogenesis and progression.[178] [179] [180] Channels can behave as oncogenes and are thus suitable as novel drug targets.[2] [88] [178] [181] [182] [183] [184] [185] [186] [187] Recent work in amphibian models has shown that depolarization of resting potential can trigger metastatic behavior in normal cells,[188] [189] while hyperpolarization (induced by ion channel misexpression, drugs, or light) can suppress tumorigenesis induced by expression of human oncogenes.[190] Depolarization of resting potential appears to be a bioelectric signature by which incipient tumor sites can be detected non-invasively.[191] Refinement of the bioelectric signature of cancer in biomedical contexts, as a diagnostic modality, is one of the possible applications of this field.[176] Excitingly, the ambivalence of polarity – depolarization as marker and hyperpolarization as treatment – make it conceptually possible to derive theragnostic (portmanteau of therapeutics with diagnostics) approaches, designed to simultaneously detect and treat early tumors, in this case based on the normalization of the membrane polarization.[190]

Pattern regulation

Recent experiments using ion channel opener/blocker drugs, as well as dominant ion channel misexpression, in a range of model species, has shown that bioelectricity, specifically, voltage gradients instruct not only stem cell behavior[192] [193] [194] [195] [196] [197] but also large-scale patterning.[198] [199] Patterning cues are often mediated by spatial gradients of cell resting potentials, or Vmem, which can be transduced into second messenger cascades and transcriptional changes by a handful of known mechanisms. These potentials are set by the function of ion channels and pumps, and shaped by gap junctional connections which establish developmental compartments (isopotential cell fields).[200] Because both gap junctions and ion channels are themselves voltage-sensitive, cell groups implement electric circuits with rich feedback capabilities. The outputs of developmental bioelectric dynamics in vivo represent large-scale patterning decisions such as the number of heads in planarian,[174] the shape of the face in frog development,[94] and the size of tails in zebrafish.[98] Experimental modulation of endogenous bioelectric prepatterns have enabled converting body regions (such as the gut) to a complete eye,[84] inducing regeneration of appendages such as tadpole tails at non-regenerative contexts,[167] [166] [165] and conversion of flatworm head shapes and contents to patterns appropriate to other species of flatworms, despite a normal genome.[171] Recent work has shown the use of physiological modeling environments for identifying predictive interventions to target bioelectric states for repair of embryonic brain defects under a range of genetic and pharmacologically induced teratologies.[85] [96]

Future research

Life is ultimately an electrochemical enterprise; research in this field is progressing along several frontiers. First is the reductive program of understanding how bioelectric signals are produced, how voltage changes in the cell membrane are able to regulate cell behavior, and what the genetic and epigenetic downstream targets of bioelectric signals are. A few mechanisms that transduce bioelectric change into alterations of gene expression are already known, including the bioelectric control of movement of small second-messenger molecules through cells, including serotonin and butyrate, voltage sensitive phosphatases, among others.[201] [202] Also known are numerous gene targets of voltage signaling, such as Notch, BMP, FGF, and HIF-1α.[123] Thus, the proximal mechanisms of bioelectric signaling within single cells are becoming well-understood, and advances in optogenetics[75] [167] [3] [203] [204] and magnetogenetics[205] continue to facilitate this research program. More challenging however is the integrative program of understanding how specific patterns of bioelectric dynamics help control the algorithms that accomplish large-scale pattern regulation (regeneration and development of complex anatomy). The incorporation of bioelectrics with chemical signaling in the emerging field of probing cell sensory perception and decision-making[206] [207] [208] [209] [210] [211] is an important frontier for future work.

Bioelectric modulation has shown control over complex morphogenesis and remodeling, not merely setting individual cell identity. Moreover, a number of the key results in this field have shown that bioelectric circuits are non-local – regions of the body make decisions based on bioelectric events at a considerable distance.[96] [99] [100] Such non-cell-autonomous events suggest distributed network models of bioelectric control;[212] [213] [214] new computational and conceptual paradigms may need to be developed to understand spatial information processing in bioelectrically active tissues. It has been suggested that results from the fields of primitive cognition and unconventional computation are relevant[213] [215] to the program of cracking the bioelectric code. Finally, efforts in biomedicine and bioengineering are developing applications such as wearable bioreactors for delivering voltage-modifying reagents to wound sites,[161] [160] and ion channel-modifying drugs (a kind of electroceutical) for repair of birth defects[85] and regenerative repair.[166] Synthetic biologists are likewise starting to incorporate bioelectric circuits into hybrid constructs.[216]

Table 1: Ion Channels and Pumps Implicated in Patterning

-ProteinMorphogenetic role or LOF (loss of function) phenotypeSpeciesReference
TRH1 K+ transporterRoot hair patterningArabidopsis[217]
Kir2.1potassium channelWing patterningDrosophila[218]
Kir7.1 K+ channelCraniofacial patterning, lung developmentMus musculus[219]
NHE2 Na+/H+ exchangerEpithelial patterningDrosophila[220]
V-ATPase proton pumpWing hair patterning, Pigmentation and brain patterning, Craniofacial patterningDrosophila, Oryzias latipes, Homo sapiens[221] [222] [223]
HCN1, Kv3.1 K+ channelsForebrain patterningMus musculus[224] [225]
KCNC1 K+ channelGrowth deficitsMus musculus[226]
TWIK-1 K+ channel (KCNK1)Cardiac (atrial) sizeMus musculus[227]
KCNJ6 K+channelKeppen-Lubinsky syndrome – craniofacial and brainHomo sapiens
KCNH1 (hEAG1) K+ channel and ATP6V1B2 V-ATPase proton pumpZimmermman-Laband and Temple-Baraitser syndrome – craniofacial and brain defects, dysplasia/aplasia of nails of thumb and great toe.Homo sapiens[228]
GLRa4 chloride channelCraniofacial anomaliesHomo sapiens[229]
KCNJ8 K+Cantu syndrome – face, heart, skeleton, brain defectsHomo sapiens[230] [231] [232]
NALCN (Na+ leak channel)Freeman-Sheldon syndrome – limbs, face, brainHomo sapiens[233]
CFTR chloride channelBilateral absence of vas deferensHomo sapiens[234] [235]
KCNC1Head/face dysmorphiasHomo sapiens[236]
KCNK9, TASK3 K+ channelsBirk-Barel Dysmorphism Syndrome – craniofacial defects, brain (cortical patterning) defectsHomo sapiens[237] [238] [239]
Kir6.2 K+ channelCraniofacial defectsHomo sapiens
KCNQ1 K+ channel (via epigenetic regulation)Hypertrophy of tongue, liver, spleen, pancreas, kidneys, adrenals, genitalia – Beckwith-Wiedemann syndrome; craniofacial and limb defects, early developmentHomo sapiens, Mus musculus, Drosophila[240] [241] [242] [243]
KCNQ1 K+ channelJervell and Lange-Nielsen syndrome - inner ear and limbHomo sapiens, Mus musculus[244] [245] [246]
Kir2.1 K+ channel (KNCJ2)Andersen-Tawil syndrome – craniofacial, limb, ribsHomo sapiens, Mus musculus[247]
GABA-A receptor (chloride channel)Angelman Syndrome - craniofacial (e.g., cleft palate) and hand patterningHomo sapiens, Mus musculus[248] [249] [250]
TMEM16A chloride channelTracheal morphogenesisMus musculus[251]
Girk2 K+ channelCerebellar development defectsMus musculus[252] [253] [254] [255]
KCNH2 K+ channelCardiac, craniofacial patterning defectsMus musculus[256]
KCNQ1 K+ channelAbnormalities of rectum, pancreas, and stomachMus musculus[257]
NaV1.2Muscle and nerve repair defectsXenopus
Kir6.1 K+ channelEye patterning defectsXenopus
V-ATPase ion pumpLeft-right asymmetry defects, muscle and nerve repairXenopus, Gallus gallus domesticus, Danio rerio
H,K-ATPase ion pumpLeft-right asymmetry defectsXenopus, Echinoidea[258] [259] [260]
Kir7.1 K+ channelMelanosome development defectsDanio rerio[261]
Kv channelsFin size regulation, heart size regulationDanio rerio, Mus musculus[262]
NaV 1.5, Na+/K+-ATPaseCardiac morphogenesisDanio rerio[263] [264]
KCNC3Dominant mutations cause cerebellar displasia in humans, and wing venation and eye defects in Drosophila.Homo sapiens, Drosophila[265]

Table 2: Gap Junctions Implicated in Patterning

Gap Junction ProteinMorphogenetic role or LOF phenotypeSpeciesReferences
InnexinsGonad and germline morphogenesisC. Elegans[266]
Innexin1,2Cuticle (epithelial) patterning, foregut developmentDrosophila[267] [268]
Innexin 2Eye sizeDrosophila[269]
Cx43Oculodentodigital dysplasia (ODDD), heart defects (outflow tract and conotruncal), left-right asymmetry randomization, Osteoblast differentiation problems, craniofacial defects, myogenesisHomo sapiens, Mus musculus, Gallus gallus domesticus[270] [271] [272] [273] [274] [275] [276] [277] [278] [279]
Cx37Lymphatic system patterningMus musculus[280] [281]
Cx45Cardiac defects (cushion patterning)Mus musculus[282] [283]
Cx50, Cx46Eye defects (differentiation and proliferation problems, especially lens),Mus musculus[284]
Cx26Cochlear development defectsMus musculus[285]
Cx41.8Pigmentation pattern defectsDanio rerio[286]
Cx43Fin size and pattern regulation
Craniofrontonasal syndrome		Danio rerio, Mus musculus[287] [288] [289] [290]
Inx4,Inx2Germline differentiation and spermatogenesisDrosophila[291]
Pannexin3Skeletal developmentMus musculus[292]

Table 3: Ion Channel Oncogenes

ProteinSpeciesReferencesCancer-role
NaV 1.5 channelHomo sapiens[293] [294] Oncogene
ERG potassium channelsHomo sapiens[295] [296] Oncogene
9 potassium channelMus musculus[297] Oncogene
Ductin (proton V-ATPase component)Mus musculus[298] Oncogene
SLC5A8 sodium/butyrate transporterHomo sapiens[299] Oncogene
KCNE2 potassium channelMus musculus[300] Oncogene
KCNQ1 potassium channelHomo sapiens, mouse[301] Oncogene
SCN5A voltage-gated sodium channelHomo sapiensOncogene
Metabotropic glutamate receptorMus musculus, Human[302] [303] Oncogene
CFTR chloride channelHomo sapiens[304] [305] Tumor suppressor
Connexin43Homo sapiens[306] Tumor suppressor
BKCaHomo sapiens[307] Oncogene
Muscarinic Acetylcholine receptorHomo sapiens, Mus musculus[308] Tumor suppressor
KCNJ3 (Girk)Homo sapiens[309] [310] Oncogene

Notes and References

  1. 25425556 . 4244194 . 2014 . Levin . M . Molecular bioelectricity: How endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo . Molecular Biology of the Cell . 25 . 24 . 3835–3850 . 10.1091/mbc.E13-12-0708 .
  2. 10.1146/annurev-cellbio-100814-125338 . 26566112 . Ion Channels in Development and Cancer . Annual Review of Cell and Developmental Biology . 31 . 231–247 . 2015 . Bates . Emily . free .
  3. 10.1146/annurev-biophys-051013-022717 . 24773017 . Bringing Bioelectricity to Light . Annual Review of Biophysics . 43 . 211–232 . 2014 . Cohen . Adam E . Venkatachalam . Veena . free .
  4. 19167986 . 2009 . Funk . R. H . Electromagnetic effects - from cell biology to medicine . Progress in Histochemistry and Cytochemistry . 43 . 4 . 177–264 . Monsees . T . Ozkucur . N . 10.1016/j.proghi.2008.07.001 .
  5. 16804297 . 2006 . Funk . R. H . Effects of electromagnetic fields on cells: Physiological and therapeutic approaches and molecular mechanisms of interaction. A review . Cells Tissues Organs . 182 . 2 . 59–78 . Monsees . T. K . 10.1159/000093061 . 10705650 .
  6. 20108228 . 2010 . Lane . N . How did LUCA make a living? Chemiosmosis in the origin of life . BioEssays . 32 . 4 . 271–280 . Allen . J. F . Martin . W . 10.1002/bies.200900131 .
  7. 23260134 . 2012 . Lane . N . The origin of membrane bioenergetics . Cell . 151 . 7 . 1406–16 . Martin . W. F . 10.1016/j.cell.2012.11.050 . free .
  8. 24801267 . 2014 . Luxardi . G . Single cell wound generates electric current circuit and cell membrane potential variations that requires calcium influx . Integr. Biol. . 6 . 7 . 662–672 . Reid . B . Maillard . P . Zhao . M . 10.1039/c4ib00041b . 7313742 .
  9. 10.1242/dev.142034 . 27827821 . 5201032 . Early bioelectric activities mediate redox-modulated regeneration . Development . 143 . 24 . 4582–4594 . 2016 . Ferreira . Fernando . Luxardi . Guillaume . Reid . Brian . Zhao . Min .
  10. Book: Robinson . K. . Messerli . M. . Electric Embryos: the embryonic epithelium as a generator of development information . McCaig . C . Nerve growth and guidance . 131–141 . Portland . 1996 .
  11. 29291972 . 5753428 . 2018 . McLaughlin . K. A . Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form . Developmental Biology . 433 . 2 . 177–189 . Levin . M . 10.1016/j.ydbio.2017.08.032 .
  12. 10.1146/annurev-bioeng-071114-040647 . 28633567 . Endogenous Bioelectric Signaling Networks: Exploiting Voltage Gradients for Control of Growth and Form . Annual Review of Biomedical Engineering . 19 . 353–387 . 2017 . Levin . Michael . Pezzulo . Giovanni . Finkelstein . Joshua M . 10478168 .
  13. Emily . Pitcairn . Kelly A. . McLaughlin . Bioelectric signaling coordinates patterning decisions during embryogenesis . Trends in Developmental Biology . 9 . 2016 . 1–9 .
  14. Pullar, C. E. The physiology of bioelectricity in development, tissue regeneration, and cancer., (CRC Press, 1996).
  15. 14711011 . 2003 . Nuccitelli . R . A role for endogenous electric fields in wound healing . Current Topics in Developmental Biology . 58 . 1–26 . 10.1016/s0070-2153(03)58001-2 . 978-0-12-153158-4 .
  16. Book: Clarke, Edwin . Nineteenth-century origins of neuroscientific concepts . 1987 . University of California Press . Jacyna, L. S. . 0-520-05694-9. Berkeley . 13456516.
  17. Book: Pera, Marcello . The ambiguous frog: the Galvani-Volta controversy on animal electricity . Princeton University Press. Tr. Mandelbaum, Jonathan . 1992 . 978-1-4008-6249-8 . Princeton, New Jersey . 889251161.
  18. Book: Piccolino, Marco; Bresadola, Marco . Shocking frogs: Galvani, Volta, and the electric origins of neuroscience . Oxford University Press . 2013 . 978-0-19-978221-5 . Oxford; New York . 859536612.
  19. Maden, M. A history of regeneration research. (Cambridge University Press, 1991).
  20. 10.1152/physrev.00020.2004 . 15987799 . Controlling Cell Behavior Electrically: Current Views and Future Potential . Physiological Reviews . 85 . 3 . 943–978 . 2005 . McCaig . Colin D. . Rajnicek . Ann M . Song . Bing . Zhao . Min .
  21. 10.1007/BF01640316 . Ueber den zeitlichen Verlauf der negativen Schwankung des Nervenstroms . About the time course of the negative fluctuation of the nerve current . de . Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere . 1 . 1 . 173–207 . 1868 . Bernstein . J . 32435163 .
  22. 10.1002/andp.18481511120 . Untersuchungen über thierische Elektricität . Investigations on animal electricity . de . Annalen der Physik und Chemie . 151 . 11 . 463–464 . 1848 . Du Bois-Reymond . Emil . 1848AnP...151..463D .
  23. 10.1016/0166-2236(83)90078-4 . The discovery of the action potential . Trends in Neurosciences . 6 . 164–8 . 1983 . Schuetze . Stephen M . 53175297 .
  24. Book: Du Bois-Reymond . Emil . Untersuchungen uber thierische Elektricitat . Investigations on Animal Electricity . de . Berlin . Georg Reimer . 1860 .
  25. Book: Finkelstein, Gabriel . Emil du Bois-Reymond: neuroscience, self, and society in nineteenth-century Germany . The MIT Press . 2013 . 978-1-4619-5032-5 . 864592470.
  26. 10.1152/ajplegacy.1903.8.4.294 . Electrical Polarity in the Hydroids . American Journal of Physiology. Legacy Content . 8 . 4 . 294–299 . 1903 . Mathews . Albert P. .
  27. Hyde . Ida H. . Differences in Electrical Potential in Developing Eggs . American Journal of Physiology. Legacy Content . 12 . 3 . 241–275 . 1904 . 10.1152/ajplegacy.1904.12.3.241.
  28. Morgan . T. H. . Dimon . Abigail C. . An examination of the problems of physiological "polarity" and of electrical polarity in the earthworm . Journal of Experimental Zoology . 1 . 2 . 331 . 1904 . 2027/hvd.32044107333023 . free . 10.1002/jez.1400010206. 1904JEZ.....1..331M .
  29. Frazee . Oren E. . The effect of electrical stimulation upon the rate of regeneration in Rana pipiens and Amblystoma jeffersonianum . Journal of Experimental Zoology . 7 . 3 . 457–475 . 1909 . 10.1002/jez.1400070304 . 1909JEZ.....7..457F .
  30. Lund . E. J. . Reversibility of morphogenetic processes in Bursaria . Journal of Experimental Zoology . 24 . 1–33 . 1917 . 1 . 10.1002/jez.1400240102. 1917JEZ....24....1L .
  31. Book: Hyman, Libbie Henrietta . Hyman's Comparative Vertebrate Anatomy . 1992-09-15 . University of Chicago Press . 978-0-226-87013-7 . 192–236.
  32. Hyman . Libbie Henrietta . Libbie Hyman . Special Articles . Science . 48 . 1247 . 518–524 . 1918 . 10.1126/science.48.1247.518 . 17795612.
  33. Lund, E. Bioelectric fiends and growth, (University of Texas Press, 1947).
  34. 10.1086/394488 . 2808474 . The Electro-Dynamic Theory of Life . The Quarterly Review of Biology . 10 . 3 . 322–333 . 1935 . Burr . H. S. . Northrop . F. S. C. . 84480134 .
  35. Marsh . G. . H. W. . Beams . Electrical control of axial polarity in a regenerating annelid . Anatomical Record . 1949 . 105 . 3 . 513–514 .
  36. 20342775 . 1947 . Marsh . G. . Electrical control of growth polarity in regenerating Dugesia tigrina . Federation Proceedings . 6 . 1 Pt 2 . 163 . Beams . H. W. .
  37. 10.1083/jcb.63.2.614 . 4421919 . 2110946 . An Ultrasensitive Vibrating Probe for Measuring Steady Extracellular Currents . The Journal of Cell Biology . 63 . 2 . 614–28 . 1974 . Jaffe . Lionel F. . Nuccitelli . Richard .
  38. Book: Jaffe . L. . Developmental Currents Voltages and Gradients . 183–215 . Developmental Order, Its Origin and Regulation . 1982 . 978-0-8451-1501-5 . registration . https://archive.org/details/developmentalord0000subt/page/183 .
  39. 10.1098/rstb.1981.0160 . 6117911 . 2395645 . The Role of Ionic Currents in Establishing Developmental Pattern . Philosophical Transactions of the Royal Society B: Biological Sciences . 295 . 1078 . 553–566 . 1981 . Jaffe . L. F . 1981RSPTB.295..553J . free .
  40. Book: Nuccitelli . Richard . 10.1021/ba-1995-0250.ch007 . Endogenous Electric Fields Measured in Developing Embryos . Electromagnetic Fields . 250 . 109–24 . Advances in Chemistry . 1995 . 978-0-8412-3135-1 .
  41. 10.1146/annurev.bb.06.060177.002305 . 326151 . Electrical Controls of Development . Annual Review of Biophysics and Bioengineering . 6 . 445–476 . 1977 . Jaffe . L. F. . Nuccitelli . R. .
  42. 3960913 . 1986 . Borgens . R. B . The role of natural and applied electric fields in neuronal regeneration and development . Progress in Clinical and Biological Research . 210 . 239–250 .
  43. Book: Borgens . Richard B. . What Is the Role of Naturally Produced Electric Current in Vertebrate Regeneration and Healing? . 76 . 245–298 . 1982 . International Review of Cytology Volume 76 . 978-0-12-364476-3 . 10.1016/S0074-7696(08)61793-3 . 6749746 .
  44. McCaig . Colin D. . Rajnicek . Ann M. . Song . Bing . Zhao . Min . Has electrical growth cone guidance found its potential? . Trends in Neurosciences . 25 . 7 . 354–9 . 2002 . 7534545 . 10.1016/S0166-2236(02)02174-4 . 12079763 .
  45. 10.1159/000224567 . 5148061 . Control of Somatic Cell Mitosis by Simulated Changes in the Transmembrane Potential Level . Oncology . 25 . 2 . 168–182 . 1971 . Cone . C. D. Jr . Tongier . M. Jr .
  46. 10.1038/newbio246110a0 . 4518935 . Stimulation of DNA Synthesis in CNS Neurones by Sustained Depolarisation . Nature New Biology . 246 . 152 . 110–111 . 1973 . Stillwell . E. F. . Cone . C. M. . Cone . C. D. .
  47. 10.1016/S0022-5193(86)80209-0 . 2443763 . Membrane potentials and sodium channels: Hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions . Journal of Theoretical Biology . 123 . 4 . 377–401 . 1986 . Binggeli . Richard . Weinstein . Roy C. . 1986JThBi.123..377B .
  48. 10.1038/144710a0 . Action Potentials Recorded from Inside a Nerve Fibre . Nature . 144 . 3651 . 710 . 1939 . Hodgkin . A. L . Huxley . A. F . 1939Natur.144..710H . 4104520 .
  49. 10.1371/journal.pone.0092594 . 24671205 . 3966808 . V-ATPase Proton Pumping Activity is Required for Adult Zebrafish Appendage Regeneration . PLOS ONE . 9 . 3 . e92594 . 2014 . Monteiro . Joana . Aires . Rita . Becker . Jörg D . Jacinto . António . Certal . Ana C . Rodríguez-León . Joaquín . 2014PLoSO...992594M . free .
  50. Book: 10.1007/978-3-540-37843-3_5 . Use of Non-Invasive Ion-Selective Microelectrode Techniques for the Study of Plant Development . Plant Electrophysiology . 109–137 . 2006 . Kunkel . Joseph G . Cordeiro . Sofia . Xu . Yu (Jeff) . Shipley . Alan M . Feijó . José A . 978-3-540-32717-2 .
  51. 27283241 . 4901296 . 2016 . Shen . Y . Diabetic cornea wounds produce significantly weaker electric signals that may contribute to impaired healing . Scientific Reports . 6 . 26525 . Pfluger . T . Ferreira . F . Liang . J . Navedo . M. F . Zeng . Q . Reid . B . Zhao . M . 10.1038/srep26525 . 2016NatSR...626525S .
  52. 10.1038/144710a0 . Action Potentials Recorded from Inside a Nerve Fibre . Nature . 144 . 3651 . 710–711 . 1939 . Hodgkin . A. L . Huxley . A. F . 1939Natur.144..710H . 4104520 .
  53. 10.1002/jcp.1030280106 . 21002959 . Membrane potentials and excitation of impaled single muscle fibers . Journal of Cellular and Comparative Physiology . 28 . 1 . 99–117 . 1946 . Graham . Judith . Gerard . R. W . 45361295 .
  54. 10.1243/17403499JNN149 . Patch clamp technique: Review of the current state of the art and potential contributions from nanoengineering . Proceedings of the Institution of Mechanical Engineers, Part N: Journal of Nanoengineering and Nanosystems . 222 . 1–11 . 2009 . Zhao . Y . Inayat . S . Dikin . D A . Singer . J H . Ruoff . R S . Troy . J B . 53316098 .
  55. 10.1002/jez.1402090106 . 314968 . Role of subdermal current shunts in the failure of frogs to regenerate . Journal of Experimental Zoology . 209 . 1 . 49–56 . 1979 . Borgens . Richard B . Vanable . Joseph W . Jaffe . Lionel F . 1979JEZ...209...49B .
  56. 10.1002/jez.1402000310 . 301554 . Bioelectricity and regeneration. I. Initiation of frog limb regeneration by minute currents . Journal of Experimental Zoology . 200 . 3 . 403–416 . 1977 . Borgens . R. B . Vanable . J. W . Jaffe . L. F . 1977JEZ...200..403B .
  57. Book: 10.1007/978-3-642-59969-9_17 . The Use of the Vibrating Probe Technique to Study Steady Extracellular Currents During Pollen Germination and Tube Growth . Fertilization in Higher Plants . 235–252 . 1999 . Shipley . A. M . Feijó . J. A . 978-3-642-64202-9 .
  58. 10.1038/nprot.2007.91 . 17406628 . Non-invasive measurement of bioelectric currents with a vibrating probe . Nature Protocols . 2 . 3 . 661–669 . 2007 . Reid . Brian . Nuccitelli . Richard . Zhao . Min . 15237787 .
  59. Kuhtreiber . W. M. . Jaffe . L. F. . 1990 . Detection of extracellular calcium gradients with a calcium-specific vibrating electrode . 2200169 . J Cell Biol . 110 . 5. 1565–1573 . 2335563 . 10.1083/jcb.110.5.1565 .
  60. 10.3791/52782 . 25993490 . 4541607 . Measurement of Extracellular Ion Fluxes Using the Ion-selective Self-referencing Microelectrode Technique . Journal of Visualized Experiments . 99 . e52782 . 2015 . Luxardi . Guillaume . Reid . Brian . Ferreira . Fernando . Maillard . Pauline . Zhao . Min .
  61. Book: 10.1016/B978-0-444-59426-6.00012-4 . 22341329 . 3494096 . Optogenetic reporters . Optogenetics: Tools for Controlling and Monitoring Neuronal Activity . 196 . 235–263 . Progress in Brain Research . 2012 . Tantama . Mathew . Hung . Yin Pun . Yellen . Gary . 978-0-444-59426-6 .
  62. 10.1364/AO.48.005528 . 19823237 . Frequency-domain fluorescence lifetime optrode system design and instrumentation without a concurrent reference light-emitting diode . Applied Optics . 48 . 29 . 5528–5536 . 2009 . Chatni . Mohammad Rameez . Li . Gang . Porterfield . David Marshall . 2009ApOpt..48.5528C .
  63. 10.1038/nprot.2007.205 . 17545984 . Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo . Nature Protocols . 2 . 6 . 1479–1489 . 2007 . Song . Bing . Gu . Yu . Pu . Jin . Reid . Brian . Zhao . Zhiqiang . Zhao . Min . 25924011 .
  64. 10.1039/C4LC00745J . 25242672 . 4437771 . ElectroTaxis-on-a-Chip (ETC): An integrated quantitative high-throughput screening platform for electrical field-directed cell migration . Lab Chip . 14 . 22 . 4398–4405 . 2014 . Zhao . Siwei . Zhu . Kan . Zhang . Yan . Zhu . Zijie . Xu . Zhengping . Zhao . Min . Pan . Tingrui .
  65. Book: 10.1109/DELTA.2010.60 . Detection of Electrical Activity of Pancreatic Beta-cells Using Micro-electrode Arrays . 2010 Fifth IEEE International Symposium on Electronic Design, Test & Applications . 233–236 . 2010 . Bornat . Yannick . Raoux . Matthieu . Boutaib . Youssef . Morin . Fabrice . Charpentier . Gilles . Lang . Jochen . Renaud . Sylvie . 3 . 978-1-4244-6025-0 . 12107878 .
  66. 10.1016/0168-1656(91)90241-M . 1367098 . Electrically controlled proliferation of human carcinoma cells cultured on the surface of an electrode . Journal of Biotechnology . 18 . 1–2 . 129–139 . 1991 . Kojima . Junichiro . Shinohara . Hiroaki . Ikariyama . Yosihito . Aizawa . Masuo . Nagaike . Kazuhiro . Morioka . Satoshi . 3.
  67. 10.1002/btpr.609 . 21574266 . 4557870 . Skeletal myotube integration with planar microelectrode arrays in vitro for spatially selective recording and stimulation: A comparison of neuronal and myotube extracellular action potentials . Biotechnology Progress . 27 . 3 . 891–5 . 2011 . Langhammer . Christopher G . Kutzing . Melinda K . Luo . Vincent . Zahn . Jeffrey D . Firestein . Bonnie L . 3.
  68. 10.1089/ten.tec.2009.0751 . 20367249 . 3003917 . Application of Low-Frequency Alternating Current Electric Fields Via Interdigitated Electrodes: Effects on Cellular Viability, Cytoplasmic Calcium, and Osteogenic Differentiation of Human Adipose-Derived Stem Cells . Tissue Engineering Part C: Methods . 16 . 6 . 1377–86 . 2010 . McCullen . Seth D . McQuilling . John P . Grossfeld . Robert M . Lubischer . Jane L . Clarke . Laura I . Loboa . Elizabeth G . 3.
  69. 10.1016/j.bios.2010.06.068 . 20656468 . DC microelectrode array for investigating the intracellular ion changes . Biosensors and Bioelectronics . 26 . 4 . 1268–1272 . 2010 . Aryasomayajula . Aditya . Derix . Jonathan . Perike . Srikant . Gerlach . Gerald . Funk . R.H .
  70. 10.1002/smll.201700789 . 28556571 . 5560653 . Controlling the Resting Membrane Potential of Cells with Conducting Polymer Microwires . Small . 13 . 27 . 1700789 . 2017 . Jayaram . Dhanya T . Luo . Qingjie . Thourson . Scott B . Finlay . Adam H . Payne . Christine K .
  71. 10.1002/(SICI)1097-0029(19990915)46:6<398::AID-JEMT8>3.0.CO;2-H . 10504217 . Self-referencing, non-invasive, ion selective electrode for single cell detection of trans-plasma membrane calcium flux . Microscopy Research and Technique . 46 . 6 . 398–417 . 1999 . Smith . Peter J.S . Hammar . Katherine . Porterfield . D. Marshall . Sanger . Richard H . Trimarchi . James R . 25177705 .
  72. Book: Peter J. S. . Smith . Richard H. . Sanger . Mark A. . Messerli . Principles, Development and Applications of Self-Referencing Electrochemical Microelectrodes to the Determination of Fluxes at Cell Membranes . . 373–405 . Adrian C. . Michael . Laura . Borland . Electrochemical Methods for Neuroscience . 2006 . CRC . 21204387 . 978-1-4200-0586-8 .
  73. 10.1038/nm0613-654 . 23744134 . Charged by GSK investment, battery of electroceuticals advance . Nature Medicine . 19 . 6 . 654 . 2013 . Sinha . Gunjan . 2260750 . free .
  74. 10.1038/496159a . 23579662 . 4179459 . A jump-start for electroceuticals . Nature . 496 . 7444 . 159–161 . 2013 . Famm . Kristoffer . Litt . Brian . Tracey . Kevin J . Boyden . Edward S . Slaoui, Moncef.
  75. 10.1387/ijdb.140207ml . 25896279 . Optogenetics in Developmental Biology: Using light to control ion flux-dependent signals in Xenopus embryos . The International Journal of Developmental Biology . 58 . 10–12 . 851–861 . 2014 . Spencer Adams . Dany . Lemire . Joan M. . Kramer . Richard H. . Levin . Michael . 10468825 . free .
  76. 10.1002/dvg.20246 . 17078061 . 3142945 . Inverse drug screens: A rapid and inexpensive method for implicating molecular targets . Genesis . 44 . 11 . 530–540 . 2006 . Adams . Dany S . Levin . Michael .
  77. 10.1242/dev.02341 . 16554361 . 3136117 . Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates . Development . 133 . 9 . 1657–1671 . 2006 . Adams . D. S. . Robinson . K. R. . Fukumoto . T. . Yuan . S . Albertson . R. C. . Yelick . P . Kuo . L. . McSweeney . M. . Levin . M. .
  78. 10.1007/s00441-012-1329-4 . 22350846 . 3869965 . Endogenous voltage gradients as mediators of cell-cell communication: Strategies for investigating bioelectrical signals during pattern formation . Cell and Tissue Research . 352 . 1 . 95–122 . 2012 . Adams . Dany S . Levin . Michael .
  79. 10.1101/pdb.top067710 . 22474653 . 4001120 . General Principles for Measuring Resting Membrane Potential and Ion Concentration Using Fluorescent Bioelectricity Reporters . Cold Spring Harbor Protocols . 2012 . 4 . 385–397 . 2012 . Adams . D. S . Levin . M .
  80. 10.1101/pdb.prot067702 . 22474652 . 4001116 . Measuring Resting Membrane Potential Using the Fluorescent Voltage Reporters DiBAC4(3) and CC2-DMPE . Cold Spring Harbor Protocols . 2012 . 4 . 459–464 . 2012 . Adams . D. S . Levin . M .
  81. 10.1016/0005-2736(84)90535-2 . 6704395 . Comparative measurements of membrane potentials with microelectrodes and voltage-sensitive dyes . Biochimica et Biophysica Acta (BBA) - Biomembranes . 771 . 2 . 208–216 . 1984 . Bräuner . Thomas . Hülser . Dieter F . Strasser . Reto J .
  82. 10.1021/jacs.6b05672 . 27428174 . 5222532 . Isomerically Pure Tetramethylrhodamine Voltage Reporters . Journal of the American Chemical Society . 138 . 29 . 9085–9088 . 2016 . Deal . Parker E . Kulkarni . Rishikesh U . Al-Abdullatif . Sarah H . Miller . Evan W .
  83. 10.1101/pdb.prot5055 . 21356693 . Live Imaging of Planarian Membrane Potential Using DiBAC4(3) . Cold Spring Harbor Protocols . 2008 . 11 . pdb.prot5055 . 2008 . Oviedo . N. J . Nicolas . C. L . Adams . D. S . Levin . M . 10468776 .
  84. 10.1242/dev.073759 . 22159581 . 3243095 . Transmembrane voltage potential controls embryonic eye patterning in Xenopus laevis . Development . 139 . 2 . 313–323 . 2011 . Pai . V. P . Aw . S . Shomrat . T . Lemire . J. M . Levin . M .
  85. 10.1038/s41467-018-03334-5 . 29519998 . 5843655 . HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns . Nature Communications . 9 . 1 . 998 . 2018 . Pai . Vaibhav P . Pietak . Alexis . Willocq . Valerie . Ye . Bin . Shi . Nian-Qing . Levin . Michael . 2018NatCo...9..998P .
  86. 10.3389/fbioe.2016.00055 . 27458581 . 4933718 . Exploring Instructive Physiological Signaling with the Bioelectric Tissue Simulation Engine . Frontiers in Bioengineering and Biotechnology . 4 . 55 . 2016 . Pietak . Alexis . Levin . Michael . free .
  87. 10.1098/rsif.2017.0425 . 28954851 . 5636277 . Bioelectric gene and reaction networks: Computational modelling of genetic, biochemical and bioelectrical dynamics in pattern regulation . Journal of the Royal Society Interface . 14 . 134 . 20170425 . 2017 . Pietak . Alexis . Levin . Michael .
  88. 10.1038/srep20403 . 26841954 . 4740742 . Bioelectrical Signals and Ion Channels in the Modeling of Multicellular Patterns and Cancer Biophysics . Scientific Reports . 6 . 20403 . 2016 . Cervera . Javier . Alcaraz . Antonio . Mafe . Salvador . 2016NatSR...620403C .
  89. 10.1038/srep35201 . 27731412 . 5059667 . The interplay between genetic and bioelectrical signaling permits a spatial regionalisation of membrane potentials in model multicellular ensembles . Scientific Reports . 6 . 35201 . 2016 . Cervera . Javier . Meseguer . Salvador . Mafe . Salvador . 2016NatSR...635201C .
  90. 10.1021/jp512900x . 25622192 . Electrical Coupling in Ensembles of Nonexcitable Cells: Modeling the Spatial Map of Single Cell Potentials . The Journal of Physical Chemistry B . 119 . 7 . 2968–2978 . 2015 . Cervera . Javier . Manzanares . Jose Antonio . Mafe . Salvador .
  91. 10.1113/expphysiol.2010.053942 . 20851856 . Optogenetic monitoring of membrane potentials . Experimental Physiology . 96 . 1 . 13–18 . 2011 . Mutoh . Hiroki . Perron . Amélie . Akemann . Walther . Iwamoto . Yuka . Knöpfel . Thomas . 5265189 . free .
  92. 10.1080/19420889.2017.1309488 . 28702127 . 5501196 . Coordinating heart morphogenesis: A novel role for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels during cardiogenesis in Xenopus laevis . Communicative & Integrative Biology . 10 . 3 . e1309488 . 2017 . Pitcairn . Emily . Harris . Hannah . Epiney . Justine . Pai . Vaibhav P . Lemire . Joan M . Ye . Bin . Shi . Nian-Qing . Levin . Michael . McLaughlin . Kelly A .
  93. 10.1242/bio.025957 . 28818840 . 5665463 . HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner . Biology Open . 6 . 10 . 1445–1457 . 2017 . Pai . Vaibhav P . Willocq . Valerie . Pitcairn . Emily J . Lemire . Joan M . Paré . Jean-François . Shi . Nian-Qing . McLaughlin . Kelly A . Levin . Michael .
  94. 10.1113/JP271930 . 26864374 . 4908029 . Bioelectric signalling via potassium channels: A mechanism for craniofacial dysmorphogenesis in KCNJ2-associated Andersen-Tawil Syndrome . The Journal of Physiology . 594 . 12 . 3245–3270 . 2016 . Adams . Dany Spencer . Uzel . Sebastien G. M . Akagi . Jin . Wlodkowic . Donald . Andreeva . Viktoria . Yelick . Pamela Crotty . Devitt-Lee . Adrian . Pare . Jean-Francois . Levin . Michael .
  95. 10.1002/dvdy.22685 . 21761475 . V-ATPase-dependent ectodermal voltage and ph regionalization are required for craniofacial morphogenesis . Developmental Dynamics . 240 . 8 . 1889–1904 . 2011 . Vandenberg . Laura N . Morrie . Ryan D . Adams . Dany Spencer . 10277013 . 205768092 . free .
  96. 10.1523/JNEUROSCI.1877-14.2015 . 25762681 . 4355204 . Endogenous Gradients of Resting Potential Instructively Pattern Embryonic Neural Tissue via Notch Signaling and Regulation of Proliferation . Journal of Neuroscience . 35 . 10 . 4366–85 . 2015 . Pai . V. P . Lemire . J. M . Pare . J.-F . Lin . G . Chen . Y . Levin . M .
  97. 10.1387/ijdb.150197ml . 26198142 . Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS . The International Journal of Developmental Biology . 59 . 7–8–9 . 327–40 . 2015 . Pai . Vaibhav P . Lemire . Joan M . Chen . Ying . Lin . Gufa . Levin . Michael . 10505512 . free .
  98. 10.1371/journal.pgen.1004080 . 24453984 . 3894163 . Bioelectric Signaling Regulates Size in Zebrafish Fins . PLOS Genetics . 10 . 1 . e1004080 . 2014 . Perathoner . Simon . Daane . Jacob M . Henrion . Ulrike . Seebohm . Guiscard . Higdon . Charles W . Johnson . Stephen L . Nüsslein-Volhard . Christiane . Harris . Matthew P . free .
  99. 10.3389/fphys.2014.00519 . 25646081 . 4298169 . Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos . Frontiers in Physiology . 5 . 519 . 2015 . Chernet . Brook T . Fields . Chris . Levin . Michael . free .
  100. 10.18632/oncotarget.1935 . 24830454 . 4102810 . Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range . Oncotarget . 5 . 10 . 3287–306 . 2014 . Chernet . Brook T . Levin . Michael .
  101. 10.1002/ajmg.a.31092 . 16419128 . Andersen-Tawil syndrome: Prospective cohort analysis and expansion of the phenotype . American Journal of Medical Genetics Part A . 140A . 4 . 312–321 . 2006 . Yoon . G . Oberoi . S . Tristani-Firouzi . M . Etheridge . S.P . Quitania . L . Kramer . J.H . Miller . B.L . Fu . Y.H . Ptáček . L.J . 33899188 .
  102. 10.1016/S0092-8674(01)00342-7 . 11371347 . Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome . Cell . 105 . 4 . 511–519 . 2001 . Plaster . Nikki M . Tawil . Rabi . Tristani-Firouzi . Martin . Canún . Sonia . Bendahhou . Saı̈d . Tsunoda . Akiko . Donaldson . Matthew R . Iannaccone . Susan T . Brunt . Ewout . Barohn . Richard . Clark . John . Deymeer . Feza . George . Alfred L . Fish . Frank A . Hahn . Angelika . Nitu . Alexandru . Ozdemir . Coskun . Serdaroglu . Piraye . Subramony . S.H . Wolfe . Gil . Fu . Ying-Hui . Ptáček . Louis J . 17015195 . free .
  103. 10.1016/j.ajhg.2014.12.011 . 25620207 . 4320262 . Keppen-Lubinsky Syndrome is Caused by Mutations in the Inwardly Rectifying K+ Channel Encoded by KCNJ6 . The American Journal of Human Genetics . 96 . 2 . 295–300 . 2015 . Masotti . Andrea . Uva . Paolo . Davis-Keppen . Laura . Basel-Vanagaite . Lina . Cohen . Lior . Pisaneschi . Elisa . Celluzzi . Antonella . Bencivenga . Paola . Fang . Mingyan . Tian . Mingyu . Xu . Xun . Cappa . Marco . Dallapiccola . Bruno .
  104. 10.1016/j.gene.2013.11.078 . 24334122 . A patient with partial trisomy 21 and 7q deletion expresses mild Down syndrome phenotype . Gene . 536 . 2 . 441–443 . 2014 . Papoulidis . I. . Papageorgiou . E. . Siomou . E. . Oikonomidou . E. . Thomaidis . L. . Vetro . A. . Zuffardi . O. . Liehr . T . Manolakos . E . Vassilis . Papadopoulos . 3 .
  105. Book: 10.1016/S0083-6729(10)83012-2 . 20831951 . Volatile Signals during Pregnancy . Pheromones . 83 . 289–304 . Vitamins & Hormones . 2010 . Vaglio . Stefano . 978-0-12-381516-3 .
  106. 10.1269/jrr.09078 . 19959877 . Pretreatment with Ascorbic Acid Prevents Lethal Gastrointestinal Syndrome in Mice Receiving a Massive Amount of Radiation . Journal of Radiation Research . 51 . 2 . 145–156 . 2010 . Yamamoto . Tetsuo . Kinoshita . Manabu . Shinomiya . Nariyoshi . Hiroi . Sadayuki . Sugasawa . Hidekazu . Matsushita . Yoshitaro . Majima . Takashi . Saitoh . Daizoh . Seki . Shuhji . 3 . 2010JRadR..51..145Y . free .
  107. 10.5507/bp.2013.077 . 24145769 . Partial trisomy and tetrasomy of chromosome 21 without down syndrome phenotype and short overview of genotype-phenotype correlation. A case report . Biomedical Papers . 158 . 2 . 321–325 . 2013 . Capkova . Pavlina . Misovicova . Nadezda . Vrbicka . Dita . free .
  108. 10.1186/s12881-016-0304-4 . 27282200 . 4901505 . Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: One clinical entity? . BMC Medical Genetics . 17 . 1 . 42 . 2016 . Mégarbané . André . Al-Ali . Rashid . Choucair . Nancy . Lek . Monko . Wang . Ena . Ladjimi . Moncef . Rose . Catherine M. . Hobeika . Remy . MacAry . Yvette . Temanni . Ramzi . Jithesh . Puthen V . Chouchane . Aouatef . Sastry . Konduru S. . Thomas . Remy . Tomei . Sara . Liu . Wei . Marincola . Francesco M. . MacArthur . Daniel . Chouchane . Lotfi . 3 . free .
  109. 27267311 . 2016 . Mastrangelo . M. . Epilepsy in KCNH1-related syndromes . Epileptic Disorders . 18 . 2 . 123–136 . Scheffer . I. E . Bramswig . N. C . Nair . L. D. . Myers . C. T . Dentici . M. L . Korenke . G. C . Schoch . K . Campeau . P. M. . White . S. M . Shashi . V . Kansagra . S . Van Essen . A. J . Leuzzi . V . 10.1684/epd.2016.0830 .
  110. 10.1007/s00439-015-1590-1 . 26264464 . 'Splitting versus lumping': Temple–Baraitser and Zimmermann–Laband Syndromes . Human Genetics . 134 . 10 . 1089–1097 . 2015 . Bramswig . Nuria C . Ockeloen . C. W . Czeschik . J. C . Van Essen . A. J . Pfundt . R . Smeitink . J . Poll-The . B. T . Engels . H . Strom . T. M . Wieczorek . D . Kleefstra . T . Lüdecke . H.-J . 14238362 .
  111. 10.1038/ng.3282 . 25915598 . Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome . Nature Genetics . 47 . 6 . 661–7 . 2015 . Kortüm . Fanny . Caputo . Viviana . Bauer . Christiane K . Stella . Lorenzo . Ciolfi . Andrea . Alawi . Malik . Bocchinfuso . Gianfranco . Flex . Elisabetta . Paolacci . Stefano . Dentici . Maria Lisa . Grammatico . Paola . Korenke . Georg Christoph . Leuzzi . Vincenzo . Mowat . David . Nair . Lal D V . Nguyen . Thi Tuyet Mai . Thierry . Patrick . White . Susan M . Dallapiccola . Bruno . Pizzuti . Antonio . Campeau . Philippe M . Tartaglia . Marco . Kutsche . Kerstin . 3 . 2108/118197 . 12060592 . free .
  112. 10.1002/ajmg.a.36301 . 24311540 . Late diagnosis of lateral meningocele syndrome in a 55-year-old woman with symptoms of joint instability and chronic musculoskeletal pain . American Journal of Medical Genetics Part A . 164 . 2 . 528–534 . 2014 . Castori . Marco . Morlino . Silvia . Ritelli . Marco . Brancati . Francesco . De Bernardo . Carmelilia . Colombi . Marina . Grammatico . Paola . 3 . 12063113 .
  113. 23646327 . 2013 . Perks . T . The orthodontic and surgical management of Zimmerman-Laband syndrome . Orthodontics . 14 . 1 . e168–176 . Popat . H. . Cronin . A. J. . Durning . P . Maggs . R . 10.11607/ortho.897.
  114. 10.17796/jcpd.36.3.k854128176u764l8 . 22838235 . Zimmermann-Laband Syndrome . Journal of Clinical Pediatric Dentistry . 36 . 3 . 297–300 . 2012 . Sawaki . K. . Mishima . K. . Sato . A. . Goda . Y . Osugi . A. . Nakano . M. . 3 .
  115. 10.1542/peds.2012-2941 . 23690510 . 3666110 . Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome . Pediatrics . 131 . 6 . e1991–1995 . 2013 . Dufendach . K. A. . Giudicessi . J. R. . Boczek . N. J. . Ackerman . M. J. .
  116. 10.1016/j.cell.2004.09.011 . 15454078 . CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism . Cell . 119 . 1 . 19–31 . 2004 . Splawski . Igor . Timothy . Katherine W . Sharpe . Leah M . Decher . Niels . Kumar . Pradeep . Bloise . Raffaella . Napolitano . Carlo . Schwartz . Peter J. . Joseph . Robert M. . Condouris . Karen . Tager-Flusberg . Helen . Priori . Silvia G. . Sanguinetti . Michael C. . Keating . Mark T. . 3 . 15325633 . free .
  117. 10.1016/j.ajog.2012.07.008 . 22917484 . 3484193 . Use of topiramate in pregnancy and risk of oral clefts . American Journal of Obstetrics and Gynecology . 207 . 5 . 405.e1–7 . 2012 . Margulis . Andrea V. . Mitchell . Allen A. . Gilboa . Suzanne M. . Werler . Martha M. . Mittleman . Murray A . Glynn . Robert J. . Hernandez-Diaz . Sonia .
  118. 10.1586/ern.10.57 . 20518610 . 2970517 . Teratogenic effects of antiepileptic drugs . Expert Review of Neurotherapeutics . 10 . 6 . 943–959 . 2014 . Hill . Denise S. . Wlodarczyk . Bogdan J. . Palacios . Ana M. . Finnell . Richard H. .
  119. Book: 10.1016/S0074-7742(06)81006-8 . 17433919 . Mechanisms of Action of Antiepileptic Drugs . The Neurobiology of Epilepsy and Aging . 81 . 85–110 . International Review of Neurobiology . 2007 . White . H. Steve . Smith . Misty D. . Wilcox . Karen S. . 978-0-12-374018-2 . https://archive.org/details/neurobiologyofep0000rams/page/85 .
  120. 10.1016/0300-483X(76)90036-6 . 996878 . Comparative study of the teratogenicity of phenobarbitone, diphenlhydatoin and carbamazepine in mice . Toxicology . 6 . 3 . 323–330 . 1976 . Fritz . H. . Müller . D. . Hess . R. .
  121. 10.1001/archpedi.1977.02120250071012 . 412416 . The Fetal Trimethadione Syndrome . American Journal of Diseases of Children . 131 . 12 . 1389–1392 . 1977 . Feldman . Gerald L. . Weaver . D. D. . Lovrien . E. W. .
  122. 10.1152/ajpregu.1982.242.3.R358 . 7065232 . The glabrous epidermis of cavies contains a powerful battery . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 242 . 3 . R358–366 . 1982 . Barker . A. T. . Jaffe . L. F. . Vanable . J. W. .
  123. 10.1063/1.1745444 . 14786543 . Vibrating Probe Electrometer for the Measurement of Bioelectric Potentials . Review of Scientific Instruments . 21 . 10 . 867–868 . 1950 . Blüh . O . Scott . B. I. H. . 1950RScI...21..867B .
  124. 10.1016/0014-4835(92)90164-N . 1521590 . Electrical fields in the vicinity of epithelial wounds in the isolated bovine eye . Experimental Eye Research . 54 . 6 . 999–1003 . 1992 . Chiang . Meicheng . Robinson . Kenneth R. . Vanable . Joseph W. .
  125. 10.1016/0012-1606(91)90239-Y . 1864462 . Intrinsic electric fields promote epithelization of wounds in the newt, Notophthalmus viridescens . Developmental Biology . 146 . 2 . 377–385 . 1991 . Chiang . Meicheng . Cragoe . Edward J . Vanable . Joseph W .
  126. 10.1096/fj.04-2325com . 15746181 . 1459277 . Wound healing in rat cornea: The role of electric currents . The FASEB Journal . 19 . 3 . 379–386 . 2005 . Reid . Brian . Song . Bing . McCaig . Colin D . Zhao . Min . free .
  127. 10.1038/nature04925 . 16871217 . Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN . Nature . 442 . 7101 . 457–460 . 2006 . Zhao . Min . Song . Bing . Pu . Jin . Wada . Teiji . Reid . Brian . Tai . Guangping . Wang . Fei . Guo . Aihua . Walczysko . Petr . Gu . Yu . Sasaki . Takehiko . Suzuki . Akira . Forrester . John V . Bourne . Henry R. . Devreotes . Peter N . McCaig . Colin D . Penninger . Josef M. . 3 . 2006Natur.442..457Z . 4391475 .
  128. 10.1038/srep26525 . 27283241 . 4901296 . Diabetic cornea wounds produce significantly weaker electric signals that may contribute to impaired healing . Scientific Reports . 6 . 26525 . 2016 . Shen . Yunyun . Pfluger . Trisha . Ferreira . Fernando . Liang . Jiebing . Navedo . Manuel F . Zeng . Qunli . Reid . Brian . Zhao . Min . 2016NatSR...626525S .
  129. Maurice, D. M. The permeability to sodium ions of the living rabbit's cornea. J Physiol 112, 367-391. Pubmed Central reference number: PMC1393020
  130. Klyce, S. D. Electrical profiles in the corneal epithelium. J Physiol 226, 407-429. Pubmed Central reference number: PMC1331188
  131. 10.1242/jcs.01341 . 15371524 . Nerve regeneration and wound healing are stimulated and directed by an endogenous electrical field in vivo . Journal of Cell Science . 117 . 20 . 4681–4690 . 2004 . Song . B . free .
  132. 10.4049/jimmunol.181.4.2465 . 18684937 . 2572691 . Lymphocyte Electrotaxis in Vitro and in Vivo . The Journal of Immunology . 181 . 4 . 2465–2471 . 2008 . Lin . F. . Baldessari . F. . Gyenge . C. C. . Sato . T . Chambers . R. D . Santiago . J. G. . Butcher . E. C. . 3 .
  133. 10.1242/jcs.113225 . 23447677 . 3666251 . The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes . Journal of Cell Science . 126 . 9 . 1942–1951 . 2013 . Yang . H.-y . Charles . R.-P . Hummler . E . Baines . D. L. . Isseroff . R. R. .
  134. 10.1016/j.cub.2013.02.047 . 23541731 . 3718648 . Electrophoresis of Cellular Membrane Components Creates the Directional Cue Guiding Keratocyte Galvanotaxis . Current Biology . 23 . 7 . 560–568 . 2013 . Allen . Greg M. . Mogilner . Alex . Theriot . Julie A. . 2013CBio...23..560A .
  135. 10.1146/annurev-cellbio-100913-013357 . 25062359 . Electrochemical Control of Cell and Tissue Polarity . Annual Review of Cell and Developmental Biology . 30 . 317–336 . 2014 . Chang . Fred . Minc . Nicolas . free .
  136. 10.1083/jcb.101.6.2023 . 3905820 . 2114002 . The responses of cells to electrical fields: A review . The Journal of Cell Biology . 101 . 6 . 2023–2037 . 1985 . Robinson . K. R. .
  137. 8834804 . Human keratinocytes migrate to the negative pole in direct current electric fields comparable to those measured in mammalian wounds . 1996 . Nishimura . K. Y . Journal of Cell Science . 109 . 1 . 199–207 . Isseroff . R. R . Nuccitelli . R . 10.1242/jcs.109.1.199.
  138. 8799828 . Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent . 1996 . Zhao . M. . Journal of Cell Science . 109 . 6 . 1405–1414 . Agius-Fernandez . A. . Forrester . J. V. . McCaig . C. D. . 10.1242/jcs.109.6.1405.
  139. 10.1385/CBB:33:1:33 . 11322511 . The Galvanotaxis Response Mechanism of Keratinocytes Can Be Modeled as a Proportional Controller . . 33 . 1 . 33–51 . 2000 . Gruler . Hans . Nuccitelli . Richard . 11731666 .
  140. 8977469 . Directed migration of corneal epithelial sheets in physiological electric fields . 1996 . Zhao . M . Investigative Ophthalmology & Visual Science . 37 . 13 . 2548–2558 . Agius-Fernandez . A . Forrester . J. V . McCaig . C. D .
  141. 10.1038/ncomms9532 . 26449415 . 4603535 . KCNJ15/Kir4.2 couples with polyamines to sense weak extracellular electric fields in galvanotaxis . Nature Communications . 6 . 8532 . 2015 . Nakajima . Ken-Ichi . Zhu . Kan . Sun . Yao-Hui . Hegyi . Bence . Zeng . Qunli . Murphy . Christopher J . Small . J. Victor . Chen-Izu . Ye . Izumiya . Yoshihiro . Penninger . Josef M . Zhao . Min . 3 . 2015NatCo...6.8532N .
  142. 10.1126/scisignal.aab0562 . 26012633 . 4470479 . A large-scale screen reveals genes that mediate electrotaxis in Dictyostelium discoideum . Science Signaling . 8 . 378 . ra50 . 2015 . Gao . Runchi . Zhao . Siwei . Jiang . Xupin . Sun . Yaohui . Zhao . Sanjun . Gao . Jing . Borleis . Jane . Willard . Stacey . Tang . Ming . Cai . Huaqing . Kamimura . Yoichiro . Huang . Yuesheng . Jiang . Jianxin . Huang . Zunxi . Mogilner . Alex . Pan . Tingrui . Devreotes . Peter N . Zhao . Min . 3.
  143. 11683396 . Directional movement of rat prostate cancer cells in direct-current electric field: Involvement of voltagegated Na+ channel activity . 2001 . Djamgoz . M. B. A . Journal of Cell Science . 114 . 14 . 2697–2705 . Mycielska . M . Madeja . Z . Fraser . S. P . Korohoda . W . 3 . 10.1242/jcs.114.14.2697.
  144. 10.1002/jcp.25259 . 26580832 . 4832312 . The Role of Kv1.2 Channel in Electrotaxis Cell Migration . Journal of Cellular Physiology . 231 . 6 . 1375–1384 . 2016 . Zhang . Gaofeng . Edmundson . Mathew . Telezhkin . Vsevolod . Gu . Yu . Wei . Xiaoqing . Kemp . Paul J . Song . Bing . 3 .
  145. 10.1016/j.jid.2016.05.129 . 27427485 . 5756539 . Kindlin-1 Regulates Keratinocyte Electrotaxis . Journal of Investigative Dermatology . 136 . 11 . 2229–2239 . 2016 . Zhang . Gaofeng . Gu . Yu . Begum . Rumena . Chen . Hongduo . Gao . Xinghua . McGrath . John A . Parsons . Maddy . Song . Bing . 3 .
  146. 10.1096/fj.01-0811fje . 11967227 . Membrane lipids, EGF receptors, and intracellular signals colocalize and are polarized in epithelial cells moving directionally in a physiological electric field . The FASEB Journal . 16 . 8 . 857–859 . 2002 . Zhao . MIN . Pu . JIN . Forrester . John V . McCaig . Colin D . free . 3 . 31682478 .
  147. 10.1073/pnas.1702526114 . 28739955 . 5559012 . Lipid rafts sense and direct electric field-induced migration . Proceedings of the National Academy of Sciences . 114 . 32 . 8568–8573 . 2017 . Lin . Bo-Jian . Tsao . Shun-hao . Chen . Alex . Hu . Shu-Kai . Chao . Ling . Chao . Pen-Hsiu Grace . 3 . 2017PNAS..114.8568L . free .
  148. Book: Maden . M. . A history of regeneration research . Cambridge University . 1991 .
  149. 10.1002/jcp.1030390203 . 14946235 . Electrical control of morphogenesis in regenerating dugesia tigrina. I. Relation of axial polarity to field strength . Journal of Cellular and Comparative Physiology . 39 . 2 . 191–213 . 1952 . Marsh . Gordon . Beams . H. W .
  150. 10.1111/j.1432-0436.1984.tb00270.x . 6526168 . Are limb development and limb regeneration both initiated by an integumentary wounding? . Differentiation . 28 . 2 . 87–93 . 1984 . Borgens . Richard B .
  151. 10.1111/j.1469-8986.1970.tb02232.x . 5499129 . Square-Wave Analysis of Skin Impedance . Psychophysiology . 7 . 2 . 262–275 . 1970 . Lykken . David T .
  152. 10.1002/ar.1091580110 . 6033441 . Induction of partial limb regeneration in Rana pipiens by galvanic stimulation . The Anatomical Record . 158 . 1 . 89–97 . 1967 . Smith . Stephen D . 22547794 .
  153. 10.1006/dbio.1996.0216 . 8812127 . Reduction of the Current of Injury Leaving the Amputation Inhibits Limb Regeneration in the Red Spotted Newt . Developmental Biology . 178 . 2 . 251–262 . 1996 . Jenkins . Lisa S . Duerstock . Bradley S . Borgens . Richard B . free .
  154. 10.1073/pnas.74.10.4528 . 270701 . 431978 . Bioelectricity and regeneration: Large currents leave the stumps of regenerating newt limbs . Proceedings of the National Academy of Sciences . 74 . 10 . 4528–32 . 1977 . Borgens . R. B . Vanable . J. W . Jaffe . L. F . 1977PNAS...74.4528B . free .
  155. 10.1002/jez.1402070206 . Small artificial currents enhance Xenopus limb regeneration . Journal of Experimental Zoology . 207 . 2 . 217–226 . 1979 . Borgens . Richard B . Vanable . Joseph W . Jaffe . Lionel F . 1979JEZ...207..217B .
  156. McCaig, C. D. Electric Fields in Vertebrate Repair., (The Physiological Society, 1989).
  157. 10.1111/j.1749-6632.1974.tb26812.x . 4531275 . Mechanical and electrical callus . Annals of the New York Academy of Sciences . 238 . 457–465 . 1974 . Yasuda . Iwao . 84676921 .
  158. 10.1143/JPSJ.12.1158 . On the Piezoelectric Effect of Bone . Journal of the Physical Society of Japan . 12 . 10 . 1158–1162 . 1957 . Fukada . Eiichi . Yasuda . Iwao . 1957JPSJ...12.1158F .
  159. Bruce M. Carlson, M. D., Ph.D. Principles of Regenerative Biology. (Academic Press, 2007).
  160. 10.1371/journal.pone.0155618 . 27257960 . 4892606 . A Tunable Silk Hydrogel Device for Studying Limb Regeneration in Adult Xenopus Laevis . PLOS ONE . 11 . 6 . e0155618 . 2016 . Golding . Anne . Guay . Justin A . Herrera-Rincon . Celia . Levin . Michael . David L. Kaplan (engineer) . Kaplan . David L . 2016PLoSO..1155618G . free .
  161. 10.1016/j.medengphy.2010.07.010 . 20708956 . 2967604 . BioDome regenerative sleeve for biochemical and biophysical stimulation of tissue regeneration . Medical Engineering & Physics . 32 . 9 . 1065–1073 . 2010 . Hechavarria . Daniel . Dewilde . Abiche . Braunhut . Susan . Levin . Michael . Kaplan . David L .
  162. 10.1038/srep18353 . 26678416 . 4683620 . Effects of electrical stimulation on rat limb regeneration, a new look at an old model . Scientific Reports . 5 . 18353 . 2015 . Leppik . Liudmila P . Froemel . Dara . Slavici . Andrei . Ovadia . Zachri N . Hudak . Lukasz . Henrich . Dirk . Marzi . Ingo . Barker . John H . 2015NatSR...518353L .
  163. 10.1016/j.ydbio.2009.08.028 . 19733557 . Electric currents in Xenopus tadpole tail regeneration . Developmental Biology . 335 . 1 . 198–207 . 2009 . Reid . Brian . Song . Bing . Zhao . Min . free .
  164. 10.4161/cib.22595 . 23802040 . 3689572 . Cracking the bioelectric code: Probing endogenous ionic controls of pattern formation . Communicative & Integrative Biology . 6 . 1 . e22595 . 2014 . Tseng . Aisun . Levin . Michael .
  165. 10.1242/dev.02812 . 17329365 . H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration . Development . 134 . 7 . 1323–1335 . 2007 . Adams . D. S . Masi . A . Levin . M . free .
  166. 10.1523/JNEUROSCI.3315-10.2010 . 20881138 . 2965411 . Induction of Vertebrate Regeneration by a Transient Sodium Current . Journal of Neuroscience . 30 . 39 . 13192–13200 . 2010 . Tseng . A.-S . Beane . W. S . Lemire . J. M . Masi . A . Levin . M .
  167. 10.1242/bio.20133665 . 23519324 . 3603412 . Light-activation of the Archaerhodopsin H+-pump reverses age-dependent loss of vertebrate regeneration: Sparking system-level controls in vivo . Biology Open . 2 . 3 . 306–313 . 2013 . Adams . D. S . Tseng . A.-S . Levin . M .
  168. 10.1242/dev.006635 . 17670787 . Smedinx-11 is a planarian stem cell gap junction gene required for regeneration and homeostasis . Development . 134 . 17 . 3121–3131 . 2007 . Oviedo . N. J . Levin . M . free .
  169. 10.1242/dev.086900 . 23250205 . 3597208 . Bioelectric signaling regulates head and organ size during planarian regeneration . Development . 140 . 2 . 313–322 . 2012 . Beane . W. S . Morokuma . J . Lemire . J. M . Levin . M .
  170. 10.1016/j.chembiol.2010.11.012 . 21276941 . 3278711 . A Chemical Genetics Approach Reveals H,K-ATPase-Mediated Membrane Voltage is Required for Planarian Head Regeneration . Chemistry & Biology . 18 . 1 . 77–89 . 2011 . Beane . Wendy S . Morokuma . Junji . Adams . Dany S . Levin . Michael .
  171. 10.3390/ijms161126065 . 26610482 . 4661923 . Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms . International Journal of Molecular Sciences . 16 . 11 . 27865–27896 . 2015 . Emmons-Bell . Maya . Durant . Fallon . Hammelman . Jennifer . Bessonov . Nicholas . Volpert . Vitaly . Morokuma . Junji . Pinet . Kaylinnette . Adams . Dany . Pietak . Alexis . Lobo . Daniel . Levin . Michael . free .
  172. 10.1016/j.ydbio.2005.09.002 . 16243308 . Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration . Developmental Biology . 287 . 2 . 314–335 . 2005 . Nogi . Taisaku . Levin . Michael . free .
  173. 10.1016/j.ydbio.2009.12.012 . 20026026 . 2823934 . Long-range neural and gap junction protein-mediated cues control polarity during planarian regeneration . Developmental Biology . 339 . 1 . 188–199 . 2010 . Oviedo . Néstor J . Morokuma . Junji . Walentek . Peter . Kema . Ido P . Gu . Man Bock . Ahn . Joo-Myung . Hwang . Jung Shan . Gojobori . Takashi . Levin . Michael .
  174. 10.1016/j.bpj.2017.04.011 . 28538159 . 5443973 . Long-Term, Stochastic Editing of Regenerative Anatomy via Targeting Endogenous Bioelectric Gradients . Biophysical Journal . 112 . 10 . 2231–2243 . 2017 . Durant . Fallon . Morokuma . Junji . Fields . Christopher . Williams . Katherine . Adams . Dany Spencer . Levin . Michael . 2017BpJ...112.2231D .
  175. 10.1242/bio.020149 . 27565761 . 5051648 . Vertically- and horizontally-transmitted memories – the fading boundaries between regeneration and inheritance in planaria . Biology Open . 5 . 9 . 1177–1188 . 2016 . Neuhof . Moran . Levin . Michael . Rechavi . Oded .
  176. 10.1088/1478-3975/9/6/065002 . 23196890 . Lobikin . Maria . Chernet . Brook . Lobo . Daniel . Levin . Michael . Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancerin vivo . Physical Biology . 9 . 6 . 2012 . 065002 . 3528107 . 2012PhBio...9f5002L .
  177. 10.3389/fphys.2013.00185 . 23882223 . 3713347 . Yang . Ming . Brackenbury . William J. . Membrane potential and cancer progression. Frontiers in Physiology . 4 . 2013 . 185 . free .
  178. 10.1517/14728222.2010.487866 . 20446866 . Gap junctions and connexins as therapeutic targets in cancer . Expert Opinion on Therapeutic Targets . 14 . 7 . 681–692 . 2010 . Kandouz . Mustapha . Batist . Gerald . 30844116 .
  179. 10.1615/CritRevOncog.v12.i3-4.30 . 17425504 . Downregulation of Gap Junctions in Cancer Cells . Critical Reviews in Oncogenesis . 12 . 3–4 . 225–256 . 2006 . Leithe . Edward . Sirnes . Solveig . Omori . Yasufumi . Rivedal . Edgar .
  180. 10.1016/S0753-3322(05)80065-4 . 16507402 . The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy . Biomedicine & Pharmacotherapy . 59 . S326–331 . 2005 . Trosko . J.E .
  181. 10.1038/nrc3635 . 24336491 . The roles of K+ channels in cancer . Nature Reviews Cancer . 14 . 1 . 39–48 . 2013 . Pardo . Luis A . Stühmer . Walter . 28497543 .
  182. 10.1083/jcb.201404136 . 25049269 . 4107787 . Targeting potassium channels in cancer . The Journal of Cell Biology . 206 . 2 . 151–162 . 2014 . Huang . Xi . Jan . Lily Yeh .
  183. 10.3390/ph3041202 . 27713296 . 4034029 . New Trends in Cancer Therapy: Targeting Ion Channels and Transporters . Pharmaceuticals . 3 . 4 . 1202–1224 . 2010 . Arcangeli . Annarosa . Becchetti . Andrea . free .
  184. 10.1098/rstb.2013.0105 . 24493753 . 3917359 . Regulation of voltage-gated sodium channel expression in cancer: Hormones, growth factors and auto-regulation . Philosophical Transactions of the Royal Society B: Biological Sciences . 369 . 1638 . 20130105 . 2014 . Fraser . S. P . Ozerlat-Gunduz . I . Brackenbury . W. J . Fitzgerald . E. M . Campbell . T. M . Coombes . R. C . Djamgoz . M. B. A .
  185. 10.1098/rstb.2013.0092 . 24493741 . 3917347 . Ion transport and cancer: From initiation to metastasis . Philosophical Transactions of the Royal Society B: Biological Sciences . 369 . 1638 . 20130092 . 2014 . Djamgoz . M. B. A . Coombes . R. C . Schwab . A .
  186. 10.1016/j.ejca.2013.03.016 . 23683551 . Ovarian cancer: Ion channel and aquaporin expression as novel targets of clinical potential . European Journal of Cancer . 49 . 10 . 2331–2344 . 2013 . Frede . Julia . Fraser . Scott P . Oskay-Özcelik . Gülten . Hong . Yeosun . Ioana Braicu . E . Sehouli . Jalid . Gabra . Hani . Djamgoz . Mustafa B.A .
  187. 10.1016/j.canlet.2012.03.036 . 22484465 . Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo . Cancer Letters . 323 . 1 . 58–61 . 2012 . Yildirim . Senay . Altun . Seyhan . Gumushan . Hatice . Patel . Anup . Djamgoz . Mustafa B.A .
  188. 10.1242/dmm.005561 . 20959630 . 3008964 . Transmembrane potential of Gly Cl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway . Disease Models & Mechanisms . 4 . 1 . 67–85 . 2010 . Blackiston . D . Adams . D. S . Lemire . J. M . Lobikin . M . Levin . M .
  189. 10.1073/pnas.0808328105 . 25465142 . 18931301 . 2575467 . Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells . Proceedings of the National Academy of Sciences . 105 . 43 . 16608–13 . 2008 . Morokuma . J . Blackiston . D . Adams . D. S . Seebohm . G . Trimmer . B . Levin . M . 2008PNAS..10516608M . free .
  190. 10.18632/oncotarget.8036 . 26988909 . 4991402 . Use of genetically encoded, light-gated ion translocators to control tumorigenesis . Oncotarget . 7 . 15 . 19575–19588 . 2016 . Chernet . Brook T . Adams . Dany S . Lobikin . Maria . Levin . Michael .
  191. 10.1242/dmm.010835 . 23471912 . 3634644 . Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model . Disease Models & Mechanisms . 6 . 3 . 595–607 . 2013 . Chernet . B. T . Levin . M .
  192. 10.1038/srep21044 . 26869018 . 4751571 . Bioelectric modulation of macrophage polarization . Scientific Reports . 6 . 21044 . 2016 . Li . Chunmei . Levin . Michael . Kaplan . David L . 2016NatSR...621044L .
  193. 10.1002/brb3.295 . 25722947 . 4321392 . Membrane potential depolarization causes alterations in neuron arrangement and connectivity in cocultures . Brain and Behavior . 5 . 1 . 24–38 . 2015 . Özkucur . Nurdan . Quinn . Kyle P . Pang . Jin C . Du . Chuang . Georgakoudi . Irene . Miller . Eric . Levin . Michael . Kaplan . David L .
  194. 10.1387/ijdb.150198ml . 26198143 . Selective depolarization of transmembrane potential alters muscle patterning and muscle cell localization in Xenopus laevis embryos . The International Journal of Developmental Biology . 59 . 7–8–9 . 303–311 . 2015 . Lobikin . Maria . Paré . Jean-François . Kaplan . David L . Levin . Michael . 10461602 . free .
  195. 10.1016/j.biomaterials.2013.05.040 . 23764116 . 3724996 . Bioelectric modulation of wound healing in a 3D in vitro model of tissue-engineered bone . Biomaterials . 34 . 28 . 6695–6705 . 2013 . Sundelacruz . Sarah . Li . Chunmei . Choi . Young Jun . Levin . Michael . Kaplan . David L .
  196. 10.1089/ten.tea.2012.0425.rev . 23738690 . 3726227 . Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells . Tissue Engineering Part A . 19 . 17–18 . 1889–1908 . 2013 . Sundelacruz . Sarah . Levin . Michael . Kaplan . David L .
  197. 10.1242/dev.011387 . 18216177 . Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242 . Development . 135 . 5 . 859–867 . 2008 . Hinard . V . Belin . D . Konig . S . Bader . C. R . Bernheim . L . free .
  198. 10.1002/bies.201100136 . 22237730 . 3430077 . Molecular bioelectricity in developmental biology: New tools and recent discoveries . BioEssays . 34 . 3 . 205–217 . 2012 . Levin . Michael .
  199. 10.1002/wsbm.1236 . 23897652 . 3841289 . Reprogramming cells and tissue patterning via bioelectrical pathways: Molecular mechanisms and biomedical opportunities . Wiley Interdisciplinary Reviews: Systems Biology and Medicine . 5 . 6 . 657–676 . 2013 . Levin . Michael .
  200. 10.1002/dneu.22405 . 27265625 . Gap junctional signaling in pattern regulation: Physiological network connectivity instructs growth and form . Developmental Neurobiology . 77 . 5 . 643–673 . 2017 . Mathews . Juanita . Levin . Michael . 10478170 . free .
  201. 10.1002/ar.22495 . 22933452 . 3442154 . Transducing Bioelectric Signals into Epigenetic Pathways During Tadpole Tail Regeneration . The Anatomical Record . 295 . 10 . 1541–1451 . 2012 . Tseng . Ai-Sun . Levin . Michael .
  202. 10.1016/j.tcb.2007.04.007 . 17498955 . Large-scale biophysics: Ion flows and regeneration . Trends in Cell Biology . 17 . 6 . 261–270 . 2007 . Levin . Michael .
  203. 10.1523/JNEUROSCI.4190-10.2010 . 21068304 . 2997431 . Toward the Second Generation of Optogenetic Tools . Journal of Neuroscience . 30 . 45 . 14998–5004 . 2010 . Knopfel . T . Lin . M. Z . Levskaya . A . Tian . L . Lin . J. Y . Boyden . E. S .
  204. 10.1146/annurev-neuro-061010-113817 . 21692661 . The Development and Application of Optogenetics . Annual Review of Neuroscience . 34 . 389–412 . 2011 . Fenno . Lief . Yizhar . Ofer . Deisseroth . Karl . 6699620 .
  205. 10.1007/s11434-015-0902-0 . 26740890 . 4692962 . Magnetogenetics: Remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor . Science Bulletin . 60 . 24 . 2107–2119 . 2015 . Long . Xiaoyang . Ye . Jing . Zhao . Di . Zhang . Sheng-Jia . 2015SciBu..60.2107L .
  206. 10.1016/j.molcel.2017.07.016 . 28826673 . 5591080 . Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control . Molecular Cell . 67 . 5 . 757–769.e5 . 2017 . Wilson . Maxwell Z . Ravindran . Pavithran T . Lim . Wendell A . Toettcher . Jared E .
  207. 10.1083/jcb.201612094 . 28003330 . 5223619 . Interrogating cellular perception and decision making with optogenetic tools . The Journal of Cell Biology . 216 . 1 . 25–28 . 2017 . Bugaj . Lukasz J . o'Donoghue . Geoff P . Lim . Wendell A .
  208. 10.1002/bies.201600090 . 27461864 . 4996742 . Cellular perception and misperception: Internal models for decision-making shaped by evolutionary experience . BioEssays . 38 . 9 . 845–849 . 2016 . Mitchell . Amir . Lim . Wendell .
  209. 10.1126/scitranslmed.3005568 . 23552369 . 3772767 . Cell-Based Therapeutics: The Next Pillar of Medicine . Science Translational Medicine . 5 . 179 . 179ps7 . 2013 . Fischbach . M. A . Bluestone . J. A . Lim . W. A .
  210. 10.1016/j.cell.2012.08.040 . 23039994 . 3498761 . Designing Synthetic Regulatory Networks Capable of Self-Organizing Cell Polarization . Cell . 151 . 2 . 320–332 . 2012 . Chau . Angela H . Walter . Jessica M . Gerardin . Jaline . Tang . Chao . Lim . Wendell A .
  211. 10.1146/annurev.biophys.050708.133652 . 20192780 . 2965450 . Rewiring Cells: Synthetic Biology as a Tool to Interrogate the Organizational Principles of Living Systems . Annual Review of Biophysics . 39 . 515–37 . 2010 . Bashor . Caleb J . Horwitz . Andrew A . Peisajovich . Sergio G . Lim . Wendell A .
  212. 10.1098/rsif.2016.0555 . 27807271 . 5134011 . Top-down models in biology: Explanation and control of complex living systems above the molecular level . Journal of the Royal Society Interface . 13 . 124 . 20160555 . 2016 . Pezzulo . Giovanni . Levin . Michael .
  213. 10.1039/c5ib00221d . 26571046 . 4667987 . Re-membering the body: Applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs . Integrative Biology . 7 . 12 . 1487–1517 . 2015 . Pezzulo . G . Levin . M .
  214. 10.1098/rsif.2014.1383 . 25788538 . 4387527 . Knowing one's place: A free-energy approach to pattern regulation . Journal of the Royal Society Interface . 12 . 105 . 20141383 . 2015 . Friston . K . Levin . M . Sengupta . B . Pezzulo . G .
  215. 10.1113/jphysiol.2014.271940 . 24882814 . 4048089 . Endogenous bioelectrical networks store non-genetic patterning information during development and regeneration . The Journal of Physiology . 592 . 11 . 2295–2305 . 2014 . Levin . Michael .
  216. 10.1103/PhysRevX.6.031001 . Optically Controlled Oscillators in an Engineered Bioelectric Tissue . Physical Review X . 6 . 3 . 2016 . McNamara . Harold M . Zhang . Hongkang . Werley . Christopher A . Cohen . Adam E . 031001 . 2016PhRvX...6c1001M . free .
  217. 11158535 . 102205 . 2001 . Rigas . S . TRH1 encodes a potassium transporter required for tip growth in Arabidopsis root hairs . The Plant Cell . 13 . 1 . 139–151 . Debrosses . G . Haralampidis . K . Vicente-Agullo . F . Feldmann . K. A . Grabov . A . Dolan . L . Hatzopoulos . P . 10.1105/tpc.13.1.139.
  218. 22949619 . 3436115 . 2012 . Dahal . G. R . An inwardly rectifying K+ channel is required for patterning . Development . 139 . 19 . 3653–3664 . Rawson . J . Gassaway . B . Kwok . B . Tong . Y . Ptácek . L. J . Bates . E . 10.1242/dev.078592 .
  219. 26402555 . 4581704 . 2015 . Villanueva . S . Cleft Palate, Moderate Lung Developmental Retardation and Early Postnatal Lethality in Mice Deficient in the Kir7.1 Inwardly Rectifying K+ Channel . PLOS ONE . 10 . 9 . e0139284 . Burgos . J. . López-Cayuqueo . K. I. . Lai . K. M. . Valenzuela . D. M. . Cid . L. P. . Sepúlveda . F. V. . 3 . 10.1371/journal.pone.0139284 . 2015PLoSO..1039284V . free .
  220. 19234454 . 2803043 . 2009 . Simons . M . Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization . Nature Cell Biology . 11 . 3 . 286–294 . Gault . W. J. . Gotthardt . D. . Rohatgi . R . Klein . T. J. . Shao . Y . Lee . H. J. . Wu . A. L. . Fang . Y . Satlin . L. M. . Dow . J. T. . Chen . J . Zheng . J . Boutros . M. . Mlodzik . M. . 3 . 10.1038/ncb1836 .
  221. 20579879 . 2010 . Hermle . T . Regulation of Frizzled-dependent planar polarity signaling by a V-ATPase subunit . Current Biology . 20 . 14 . 1269–1276 . Saltukoglu . D. . Grünewald . J. . Walz . G. . Simons . M. . 3 . 10.1016/j.cub.2010.05.057 . 15407237 . free . 2010CBio...20.1269H .
  222. 24225653 . 3827601 . 2013 . Müller . C. . The medaka mutation tintachina sheds light on the evolution of V-ATPase B subunits in vertebrates . Scientific Reports . 3 . 3217 . Maeso . I . Wittbrodt . J. . Martínez-Morales . J. R. . 10.1038/srep03217 . 2013NatSR...3E3217M .
  223. 12566520 . 1735376 . 2003 . Borthwick . K. J. . A phenocopy of CAII deficiency: A novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis . Journal of Medical Genetics . 40 . 2 . 115–121 . Kandemir . N. . Topaloglu . R. . Kornak . U. . Bakkaloglu . A. . Yordam . N . Ozen . S. . Mocan . H. . Shah . G. N. . Sly . W. S. . Karet . F. E. . 3 . 10.1136/jmg.40.2.115.
  224. 10.1085/jgp.201511461 . 26216856 . 4516783 . A new standard: A review of Handbook of Ion Channels . The Journal of General Physiology . 146 . 2 . 119–121 . 2015 . Aldrich . Richard W. .
  225. 23821603 . 3829632 . 2013 . Duque . A. . Expression of Kv1.3 potassium channels regulates density of cortical interneurons . Developmental Neurobiology . 73 . 11 . 841–855 . Gazula . V. R. . Kaczmarek . L. K. . 10.1002/dneu.22105 .
  226. Zheng, J. a. T., M. C. Handbook of ion channels. (CRC Press, 2015).
  227. 27103460 . 2016 . Christensen . A. H . The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size . Journal of Molecular and Cellular Cardiology . 97 . 24–35 . Chatelain . F. C. . Huttner . I. G. . Olesen . M. S. . Soka . M. . Feliciangeli . S . Horvat . C . Santiago . C. F. . Vandenberg . J. I . Schmitt . N. . Olesen . S. P. . Lesage . F. . Fatkin . D. . 3 . 10.1016/j.yjmcc.2016.04.006 .
  228. 25420144 . 2015 . Simons . C . Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy . Nature Genetics . 47 . 1 . 73–77 . Rash . L. D. . Crawford . J . Ma . L . Cristofori-Armstrong . B. . Miller . D . Ru . K. . Baillie . G. J . Alanay . Y. . Jacquinet . A. . Debray . F. G. . Verloes . A . Shen . J. . Yesil . G. . Guler . S. . Yuksel . A. . Cleary . J. G. . Grimmond . S. M. . McGaughran . J. . King . G. F. . Gabbett . M. T . Taft . R. J. . 3 . 10.1038/ng.3153 . 52799681 .
  229. 27506666 . 4979147 . 2016 . Labonne . J. D. . A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies . BMC Neurology . 16 . 132 . Graves . T. D. . Shen . Y. . Jones . J. R. . Kong . I. K. . Layman . L. C. . Kim . H. G. . 3 . 10.1186/s12883-016-0642-z . free .
  230. 24352916 . 2014 . Hiraki . Y. . Aortic aneurysm and craniosynostosis in a family with Cantu syndrome . American Journal of Medical Genetics Part A . 164A . 1 . 231–236 . Miyatake . S. . Hayashidani . M. . Nishimura . Y. . Matsuura . H. . Kamada . M. . Kawagoe . T. . Yunoki . K. . Okamoto . N . Yofune . H . Nakashima . M. . Tsurusaki . Y. . Satisu . H . Murakami . A . Miyake . N. . Nishimura . G. . Matsumoto . N. . 3 . 10.1002/ajmg.a.36228 . 73121 .
  231. 24700710 . 4277879 . 2014 . Cooper . P. E . Cantú syndrome resulting from activating mutation in the KCNJ8 gene . Human Mutation . 35 . 7 . 809–813 . Reutter . H. . Woelfle . J. . Engels . H. . Grange . D. K . Van Haaften . G . Van Bon . B. W . Hoischen . A. . Nichols . C. G. . 3 . 10.1002/humu.22555 .
  232. 24176758 . 3902017 . 2013 . Brownstein . C. A. . Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition . European Journal of Medical Genetics . 56 . 12 . 678–682 . Towne . M. C. . Luquette . L. J . Harris . D. J . Marinakis . N. S . Meinecke . P . Kutsche . K. . Campeau . P. M . Yu . T. W. . Margulies . D. M. . Agrawal . P. B. . Beggs . A. H. . 3 . 10.1016/j.ejmg.2013.09.009 .
  233. 25683120 . 4375444 . 2015 . Chong . J. X. . De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay . The American Journal of Human Genetics . 96 . 3 . 462–473 . McMillin . M. J. . Shively . K. M. . Beck . A. E. . Marvin . C. T. . Armenteros . J. R. . Buckingham . K. J. . Nkinsi . N. T. . Boyle . E. A . Berry . M. N. . Bocian . M. . Foulds . N. . Uzielli . M. L. . Haldeman-Englert . C. . Hennekam . R. C. . Kaplan . P . Kline . A. D. . Mercer . C. L. . Nowaczyk . M. J. . Klein Wassink-Ruiter . J. S . McPherson . E. W . Moreno . R. A. . Scheuerle . A. E . Shashi . V . Stevens . C. A . Carey . J. C. . Monteil . A . Lory . P . Tabor . H. K. . Smith . J. D. . 3 . 10.1016/j.ajhg.2015.01.003 .
  234. 16272798 . 2005 . Uzun . S . Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens . The Tohoku Journal of Experimental Medicine . 207 . 4 . 279–285 . Gökçe . S. . Wagner . K. . 10.1620/tjem.207.279 . free .
  235. 16840743 . 2648063 . 2006 . Wilschanski . M. . Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials . American Journal of Respiratory and Critical Care Medicine . 174 . 7 . 787–794 . Dupuis . A. . Ellis . L. . Jarvi . K. . Zielenski . J. . Tullis . E. . Martin . S. . Corey . M . Tsui . L. C. . Durie . P. . 3 . 10.1164/rccm.200509-1377OC .
  236. 28145425 . 5437909 . 2017 . Poirier . K. . Loss of Function of KCNC1 is associated with intellectual disability without seizures . European Journal of Human Genetics . 25 . 5 . 560–564 . Viot . G. . Lombardi . L. . Jauny . C. . Billuart . P. . Bienvenu . T. . 10.1038/ejhg.2017.3 .
  237. 24342771 . 2014 . Veale . E. L . Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome . Molecular Pharmacology . 85 . 3 . 397–407 . Hassan . M. . Walsh . Y. . Al-Moubarak . E. . Mathie . A. . 3 . 10.1124/mol.113.090530 . 14790826 .
  238. 18678320 . 2495061 . 2008 . Barel . O . Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9 . The American Journal of Human Genetics . 83 . 2 . 193–199 . Shalev . S. A. . Ofir . R. . Cohen . A . Zlotogora . J . Shorer . Z. . Mazor . G. . Finer . G . Khateeb . S . Zilberberg . N . Birk . O. S. . 3 . 10.1016/j.ajhg.2008.07.010 .
  239. 10.1056/NEJMoa032922 . 15115830 . Activating Mutations in the Gene Encoding the ATP-Sensitive Potassium-Channel Subunit Kir6.2 and Permanent Neonatal Diabetes . New England Journal of Medicine . 350 . 18 . 1838–1849 . 2004 . Gloyn . Anna L . Pearson . Ewan R . Antcliff . Jennifer F. . Proks . Peter . Bruining . G. Jan . Slingerland . Annabelle S . Howard . Neville . Srinivasan . Shubha . Silva . José M. C. L. . Molnes . Janne . Edghill . Emma L . Frayling . Timothy M. . Temple . I. Karen . MacKay . Deborah . Shield . Julian P. H. . Sumnik . Zdenek . Van Rhijn . Adrian . Wales . Jerry K. H. . Clark . Penelope . Gorman . Shaun . Aisenberg . Javier . Ellard . Sian . Njølstad . Pål R. . Ashcroft . Frances M. . Hattersley . Andrew T. . 3 .
  240. 11120752 . 387258 . 2000 . Lee . M. P. . Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice . Journal of Clinical Investigation . 106 . 12 . 1447–1455 . Ravenel . J. D. . Hu . R. J. . Lustig . L. R. . Tomaselli . G . Berger . R. D . Brandenburg . S. A. . Litzi . T. J. . Bunton . T. E. . Limb . C . Francis . H . Gorelikow . M . Gu . H . Washington . K . Argani . P . Goldenring . J. R. . Coffey . R. J . Feinberg . A. P. . 3. 10.1172/JCI10897 .
  241. 11751681 . 2001 . Weksberg . R . Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1 . Human Molecular Genetics . 10 . 26 . 2989–3000 . Nishikawa . J. . Caluseriu . O. . Fei . Y. L . Shuman . C. . Wei . C. . Steele . L. . Cameron . J. . Smith . A. . Ambus . I. . Li . M. . Ray . P. N. . Sadowski . P. . Squire . J. . 3 . 10.1093/hmg/10.26.2989. free .
  242. 10710224 . 2000 . Moore . E. S. . Heterogeneity in Wiedemann-Beckwith syndrome: Anthropometric evidence . American Journal of Medical Genetics . 90 . 4 . 283–290 . Ward . R. E . Escobar . L. F. . Carlin . M. E. . 10.1002/(SICI)1096-8628(20000214)90:4<283::AID-AJMG4>3.0.CO;2-F .
  243. 16267222 . 2005 . Wen . H. . A Drosophila KCNQ channel essential for early embryonic development . Journal of Neuroscience . 25 . 44 . 10147–10156 . Weiger . T. M. . Ferguson . T. S. . Shahidullah . M. . Scott . S. S. . Levitan . I. B. . 3 . 10.1523/JNEUROSCI.3086-05.2005 . 6725806 . free .
  244. 15891643 . 2005 . Rivas . A . Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: A model of Jervell and Lange-Nielsen syndrome . Otology & Neurotology . 26 . 3 . 415–424 . Francis . H. W . 10.1097/01.mao.0000169764.00798.84. 1700736 .
  245. 15498462 . 2004 . Casimiro . M. C . Targeted point mutagenesis of mouse Kcnq1: Phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans . Genomics . 84 . 3 . 555–564 . Knollmann . B. C . Yamoah . E. N . Nie . L . Vary Jr . J. C . Sirenko . S. G . Greene . A. E . Grinberg . A . Huang . S. P . Ebert . S. N . Pfeifer . K . 10.1016/j.ygeno.2004.06.007 .
  246. 9312006 . 1170178 . 1997 . Chouabe . C . Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias . The EMBO Journal . 16 . 17 . 5472–5479 . Neyroud . N . Guicheney . P . Lazdunski . M. . Romey . G. . Barhanin . J. . 3 . 10.1093/emboj/16.17.5472 .
  247. 14522976 . 2003 . Bendahhou . S . Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome . Journal of Biological Chemistry . 278 . 51 . 51779–51785 . Donaldson . M. R . Plaster . N. M . Tristani-Firouzi . M . Fu . Y. H . Ptácek . L. J. . 3 . 10.1074/jbc.M310278200 . free .
  248. 7581464 . 1995 . Culiat . C. T .. Deficiency of the beta 3 subunit of the type a gamma-aminobutyric acid receptor causes cleft palate in mice . Nature Genetics . 11 . 3 . 344–346 . Stubbs . L. J. . Woychik . R. P . Russell . L. B. . Johnson . D. K. . Rinchik . E. M. . 10.1038/ng1195-344 . 19397785 .
  249. 4088436 . 1985 . Wee . E. L . GABA uptake in embryonic palate mesenchymal cells of two mouse strains . Neurochemical Research . 10 . 12 . 1673–1688 . Zimmerman . E. F . 10.1007/bf00988609. 26049392 .
  250. 9108119 . 20582 . 1997 . Homanics . G. E . Mice devoid of gamma-aminobutyrate type a receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior . Proceedings of the National Academy of Sciences of the United States of America . 94 . 8 . 4143–4148 . Delorey . T. M. . Firestone . L. L. . Quinlan . J. J . Handforth . A. . Harrison . N. L. . Krasowski . M. D. . Rick . C. E . Korpi . E. R. . Mäkelä . R. . Brilliant . M. H. . Hagiwara . N . Ferguson . C . Snyder . K. . Olsen . R. W. . 3 . 10.1073/pnas.94.8.4143 . 1997PNAS...94.4143H . free .
  251. 18585372 . 2008 . Rock . J. R. . The transmembrane protein TMEM16A is required for normal development of the murine trachea . Developmental Biology . 321 . 1 . 141–149 . Futtner . C. R. . Harfe . B. D. . 10.1016/j.ydbio.2008.06.009 . free .
  252. 4128371 . 1973 . Rakic . P . Sequence of developmental abnormalities leading to granule cell deficit in cerebellar cortex of weaver mutant mice . The Journal of Comparative Neurology . 152 . 2 . 103–132 . Sidman . R. L. . 10.1002/cne.901520202 . 6553698 .
  253. 4509657 . 433223 . 1973 . Rakic . P . Weaver mutant mouse cerebellum: Defective neuronal migration secondary to abnormality of Bergmann glia . Proceedings of the National Academy of Sciences of the United States of America . 70 . 1 . 240–244 . Sidman . R. L . 10.1073/pnas.70.1.240. 1973PNAS...70..240R . free .
  254. 3528411 . 1986 . Hatten . M. E . Weaver mouse cerebellar granule neurons fail to migrate on wild-type astroglial processes in vitro . The Journal of Neuroscience . 6 . 9 . 2676–2683 . Liem . R. K . Mason . C. A . 10.1523/jneurosci.06-09-02676.1986. 6568692. free .
  255. 7550338 . 1995 . Patil . N . A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation . Nature Genetics . 11 . 2 . 126–129 . Cox . D. R . Bhat . D . Faham . M . Myers . R. M . Peterson . A. S . 10.1038/ng1095-126 . 23470275 .
  256. 18948620 . 2774899 . 2008 . Teng . G. Q. . Homozygous missense N629D hERG (KCNH2) potassium channel mutation causes developmental defects in the right ventricle and its outflow tract and embryonic lethality . Circulation Research . 103 . 12 . 1483–1491 . Zhao . X. . Lees-Miller . J. P. . Quinn . F. R. . Li . P. . Rancourt . D. E. . London . B. . Cross . J. C. . Duff . H. J. . 10.1161/CIRCRESAHA.108.177055 .
  257. 23975432 . 3935979 . 2014 . Than . B. L . The role of KCNQ1 in mouse and human gastrointestinal cancers . Oncogene . 33 . 29 . 3861–3868 . Goos . J. A. . Sarver . A. L. . O'Sullivan . M. G. . Rod . A . Starr . T. K . Fijneman . R. J. . Meijer . G. A . Zhao . L . Zhang . Y . Largaespada . D. A. . Scott . P. M. . Cormier . R. T. . 3 . 10.1038/onc.2013.350 .
  258. 24671205 . 3966808 . 2014 . Monteiro . J . V-ATPase proton pumping activity is required for adult zebrafish appendage regeneration . PLOS ONE . 9 . 3 . e92594 . Aires . R . Becker . J. D . Jacinto . A . Certal . A. C . Rodríguez-León . J . 10.1371/journal.pone.0092594 . 2014PLoSO...992594M . free .
  259. 12372302 . 2002 . Levin . M . Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning . Cell . 111 . 1 . 77–89 . Thorlin . T . Robinson . K. R . Nogi . T . Mercola . M . 10.1016/s0092-8674(02)00939-x. 2502945 . free .
  260. 15992548 . 2005 . Duboc . V . Left-right asymmetry in the sea urchin embryo is regulated by nodal signaling on the right side . Developmental Cell . 9 . 1 . 147–158 . Röttinger . E . Lapraz . F . Besnardeau . L . Lepage . T . 3 . 10.1016/j.devcel.2005.05.008 . free .
  261. 17121467 . 1657052 . 2006 . Iwashita . M . Pigment pattern in jaguar/obelix zebrafish is caused by a Kir7.1 mutation: Implications for the regulation of melanosome movement . PLOS Genetics . 2 . 11 . e197 . Watanabe . M . Ishii . M . Chen . T . Johnson . S. L. . Kurachi . Y. . Okada . N. . Kondo . S. . 3 . 10.1371/journal.pgen.0020197 . free .
  262. 27038296 . 4827621 . 2016 . Tur . J . Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts . Experimental Physiology . 101 . 4 . 494–508 . Chapalamadugu . K. C . Padawer . T . Badole . S. L . Kilfoil Pj . 2nd . Bhatnagar . A . Tipparaju . S. M . 10.1113/EP085405 .
  263. 20339120 . 2869449 . 2010 . Chopra . S. S . Voltage-gated sodium channels are required for heart development in zebrafish . Circulation Research . 106 . 8 . 1342–1350 . Stroud . D. M . Watanabe . H . Bennett . J. S . Burns . C. G . Wells . K. S . Yang . T . Zhong . T. P . Roden . D. M . 10.1161/CIRCRESAHA.109.213132 .
  264. 14602677 . 2003 . Shu . X . Na,K-ATPase is essential for embryonic heart development in the zebrafish . Development . 130 . 25 . 6165–6173 . Cheng . K . Patel . N . Chen . F . Joseph . E . Tsai . H. J . Chen . J. N. . 3 . 10.1242/dev.00844 . free .
  265. 28467418 . 5414954 . 2017 . Khare . S . A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking . PLOS ONE . 12 . 5 . e0173565 . Nick . J. A . Zhang . Y . Galeano . K . Butler . B . Khoshbouei . H . Rayaprolu . S . Hathorn . T . Ranum . L. P. W . Smithson . L . Golde . T. E . Paucar . M . Morse . R . Raff . M . Simon . J . Nordenskjöld . M . Wirdefeldt . K . Rincon-Limas . D. E . Lewis . J . Kaczmarek . L. K . Fernandez-Funez . P . Nick . H. S . Waters . M. F. . 3 . 10.1371/journal.pone.0173565 . 2017PLoSO..1273565K . free .
  266. 25195067 . 4224157 . 2014 . Starich . T. A. . Two classes of gap junction channels mediate soma-germline interactions essential for germline proliferation and gametogenesis in Caenorhabditis elegans . Genetics . 198 . 3 . 1127–1153 . Hall . D. H. . Greenstein . D. . 10.1534/genetics.114.168815 .
  267. 15047872 . 420120 . 2004 . Bauer . R . Gap junction channel protein innexin 2 is essential for epithelial morphogenesis in the Drosophila embryo . Molecular Biology of the Cell . 15 . 6 . 2992–3004 . Lehmann . C . Martini . J . Eckardt . F . Hoch . M . 10.1091/mbc.E04-01-0056 .
  268. 11956317 . The Drosophila gap junction channel gene innexin 2 controls foregut development in response to Wingless signalling . 2002 . Bauer . R . Journal of Cell Science . 115 . Pt 9 . 1859–1867 . Lehmann . C . Fuss . B . Eckardt . F . Hoch . M. . 3 . 10.1242/jcs.115.9.1859.
  269. 26455410 . 2015 . Richard . M. . Drosophila eye size is determined by Innexin 2-dependent Decapentaplegic signalling . Developmental Biology . 408 . 1 . 26–40 . Hoch . M . 10.1016/j.ydbio.2015.10.011 . free .
  270. 16378922 . 2005 . Debeer . P . Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD) . European Journal of Medical Genetics . 48 . 4 . 377–387 . Van Esch . H . Huysmans . C . Pijkels . E . De Smet . L . Van De Ven . W . Devriendt . K . Fryns . J. P . 10.1016/j.ejmg.2005.05.003 .
  271. 14974090 . 2004 . Pizzuti . A . A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype . Human Mutation . 23 . 3 . 286 . Flex . E . Mingarelli . R . Salpietro . C . Zelante . L . Dallapiccola . B . 10.1002/humu.9220 . 13345970 . free .
  272. 9118799 . 1997 . Ewart . J. L . Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene . Development . 124 . 7 . 1281–1292 . Cohen . M. F . Meyer . R. A . Huang . G. Y . Wessels . A . Gourdie . R. G . Chin . A. J . Park . S. M . Lazatin . B. O . Villabon . S . Lo . C. W . 10.1242/dev.124.7.1281 . 189036 .
  273. 7892609 . 1995 . Reaume . A. G . Cardiac malformation in neonatal mice lacking connexin43 . Science . 267 . 5205 . 1831–1834 . De Sousa . P. A . Kulkarni . S . Langille . B. L . Zhu . D . Davies . T. C . Juneja . S. C . Kidder . G. M . Rossant . J . 10.1126/science.7892609. 1995Sci...267.1831R .
  274. 7715640 . 1995 . Britz-Cunningham . S. H . Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality . New England Journal of Medicine . 332 . 20 . 1323–1329 . Shah . M. M . Zuppan . C. W . Fletcher . W. H . 10.1056/NEJM199505183322002 . free .
  275. 18424255 . 2441851 . 2008 . Civitelli . R . Cell-cell communication in the osteoblast/osteocyte lineage . Archives of Biochemistry and Biophysics . 473 . 2 . 188–192 . 10.1016/j.abb.2008.04.005 .
  276. 10518488 . 1999 . Levin . M . Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node . Development . 126 . 21 . 4703–4714 . Mercola . M . 10.1242/dev.126.21.4703 .
  277. 10079509 . 1999 . Becker . D. L . Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach . Developmental Genetics . 24 . 1–2 . 33–42 . McGonnell . I . Makarenkova . H. P . Patel . K . Tickle . C . Lorimer . J . Green . C. R . 10.1002/(SICI)1520-6408(1999)24:1/2<33::AID-DVG5>3.0.CO;2-F .
  278. 11076975 . 2169447 . 2000 . Lecanda . F . Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction . The Journal of Cell Biology . 151 . 4 . 931–944 . Warlow . P. M . Sheikh . S . Furlan . F . Steinberg . T. H . Civitelli . R . 10.1083/jcb.151.4.931.
  279. 14681056 . 2003 . Araya . R . Presence and importance of connexin43 during myogenesis . Cell Communication & Adhesion . 10 . 4–6 . 451–456 . Eckardt . D . Riquelme . M. A . Willecke . K . Sáez . J. C . 10.1080/cac.10.4-6.451.456. 33491307 . 10533/174413 . free .
  280. 21515254 . 3134316 . 2011 . Kanady . J. D . Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax . Developmental Biology . 354 . 2 . 253–266 . Dellinger . M. T . Munger . S. J . Witte . M. H . Simon . A. M . 10.1016/j.ydbio.2011.04.004 .
  281. 26079578 . 4529811 . 2015 . Kanady . J. D . Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling . Developmental Biology . 405 . 1 . 33–46 . Munger . S. J . Witte . M. H . Simon . A. M . 10.1016/j.ydbio.2015.06.004 .
  282. 10903175 . 2000 . Kumai . M . Loss of connexin45 causes a cushion defect in early cardiogenesis . Development . 127 . 16 . 3501–3512 . Nishii . K . Nakamura . K . Takeda . N . Suzuki . M . Shibata . Y . 10.1242/dev.127.16.3501 .
  283. 11673050 . 2001 . Nishii . K . Regulation of the epithelial-mesenchymal transformation through gap junction channels in heart development . Trends in Cardiovascular Medicine . 11 . 6 . 213–218 . Kumai . M . Shibata . Y . 10.1016/s1050-1738(01)00103-7.
  284. 11786642 . 2002 . White . T. W . Unique and redundant connexin contributions to lens development . Science . 295 . 5553 . 319–320 . 10.1126/science.1067582 . 2002Sci...295..319W . 25744002 .
  285. 25251605 . 2015 . Chang . Q . Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing . Neurobiology of Disease . 73 . 418–427 . Tang . W . Kim . Y . Lin . X . 10.1016/j.nbd.2014.09.005 . 207068577 .
  286. 16845369 . 1559663 . 2006 . Watanabe . M . Spot pattern of leopard Danio is caused by mutation in the zebrafish connexin41.8 gene . EMBO Reports . 7 . 9 . 893–897 . Iwashita . M . Ishii . M . Kurachi . Y . Kawakami . A . Kondo . S . Okada . N . 10.1038/sj.embor.7400757 .
  287. 15649473 . 2005 . Iovine . M. K . Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins . Developmental Biology . 278 . 1 . 208–219 . Higgins . E. P . Hindes . A . Coblitz . B . Johnson . S. L . 10.1016/j.ydbio.2004.11.005 . free .
  288. 16968134 . 1563491 . 2006 . Davy . A . Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome . PLOS Biology . 4 . 10 . e315 . Bush . J. O . Soriano . P . 10.1371/journal.pbio.0040315 . free .
  289. 19150347 . 2913275 . 2009 . Sims Jr . K . Connexin43 regulates joint location in zebrafish fins . Developmental Biology . 327 . 2 . 410–418 . Eble . D. M . Iovine . M. K . 10.1016/j.ydbio.2008.12.027 .
  290. 18406403 . 2429987 . 2008 . Hoptak-Solga . A. D . Connexin43 (GJA1) is required in the population of dividing cells during fin regeneration . Developmental Biology . 317 . 2 . 541–548 . Nielsen . S . Jain . I . Thummel . R . Hyde . D. R . Iovine . M. K . 10.1016/j.ydbio.2008.02.051 .
  291. 26116660 . 2015 . Smendziuk . C. M . Bi-directional gap junction-mediated soma-germline communication is essential for spermatogenesis . Development . 142 . 15 . 2598–2609 . Messenberg . A . Vogl . A. W . Tanentzapf . G . 10.1242/dev.123448 . 6514411.
  292. 26183770 . 2015 . Oh . S. K . Pannexin 3 is required for normal progression of skeletal development in vertebrates . The FASEB Journal . 29 . 11 . 4473–4484 . Shin . J. O . Baek . J. I . Lee . J . Bae . J. W . Ankamerddy . H . Kim . M. J . Huh . T. L . Ryoo . Z. Y . Kim . U. K . Bok . J . Lee . K. Y . 10.1096/fj.15-273722 . free . 8219978 .
  293. 19835862 . 2009 . Onkal . R . Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer . European Journal of Pharmacology . 625 . 1–3 . 206–219 . Djamgoz . M. B . 10.1016/j.ejphar.2009.08.040 .
  294. 20651255 . 2936697 . 2010 . House . C. D . Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion . Cancer Research . 70 . 17 . 6957–6967 . Vaske . C. J . Schwartz . A. M . Obias . V . Frank . B . Luu . T . Sarvazyan . N . Irby . R . Strausberg . R. L . Hales . T. G . Stuart . J. M . Lee . N. H . 10.1158/0008-5472.CAN-10-1169 .
  295. 25945833 . 5312283 . 2016 . Perez-Neut . M . HERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism . Oncotarget . 7 . 37 . 58893–58902 . Rao . V. R . Gentile . S . 10.18632/oncotarget.3797.
  296. 23744352 . 3698542 . 2013 . Lansu . K . Potassium channel activation inhibits proliferation of breast cancer cells by activating a senescence program . Cell Death & Disease . 4 . 6 . e652 . Gentile . S . 10.1038/cddis.2013.174 .
  297. 12782791 . 164668 . 2003 . Pei . L . Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function . Proceedings of the National Academy of Sciences . 100 . 13 . 7803–7807 . Wiser . O . Slavin . A . Mu . D . Powers . S . Jan . L. Y . Hoey . T . 10.1073/pnas.1232448100 . 2003PNAS..100.7803P . free .
  298. 10.1038/sj.onc.1202092 . 9796696 . Induction of cell transformation by mutated 16K vacuolar H+-atpase (ductin) is accompanied by down-regulation of gap junctional intercellular communication and translocation of connexin 43 in NIH3T3 cells . Oncogene . 17 . 13 . 1673–1680 . 1998 . Saito . Tsuyoshi . Schlegel . Richard . Andresson . Thirkell . Yuge . Louis . Yamamoto . Masao . Yamasaki . Hiroshi . free .
  299. 16375929 . 2006 . Gupta . N . SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter . Life Sciences . 78 . 21 . 2419–2425 . Martin . P. M . Prasad . P. D . Ganapathy . V . 10.1016/j.lfs.2005.10.028 .
  300. 20625512 . 2897890 . 2010 . Roepke . T. K . Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia . PLOS ONE . 5 . 7 . e11451 . Purtell . K . King . E. C . La Perle . K. M . Lerner . D. J . Abbott . G. W . 10.1371/journal.pone.0011451 . 2010PLoSO...511451R . free .
  301. 9020845 . 1997 . Lee . M. P . Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements . Nature Genetics . 15 . 2 . 181–185 . Hu . R. J . Johnson . L. A . Feinberg . A. P. . 3 . 10.1038/ng0297-181 . 24715509 .
  302. 23085756 . 3910169 . 2013 . Martino . J. J . Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells . Oncogene . 32 . 37 . 4366–4376 . Wall . B. A . Mastrantoni . E . Wilimczyk . B. J . La Cava . S. N . Degenhardt . K . White . E . Chen . S . 10.1038/onc.2012.471 .
  303. 21681448 . 3898178 . 2012 . Speyer . C. L . Metabotropic glutamate receptor-1: A potential therapeutic target for the treatment of breast cancer . Breast Cancer Research and Treatment . 132 . 2 . 565–573 . Smith . J. S . Banda . M . Devries . J. A . Mekani . T . Gorski . D. H. . 3 . 10.1007/s10549-011-1624-x .
  304. 23916755 . 2013 . Zhang . J. T . Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1833 . 12 . 2961–2969 . Jiang . X. H . Xie . C . Cheng . H . Da Dong . J . Wang . Y . Fok . K. L . Zhang . X. H . Sun . T. T . Tsang . L. L . Chen . H . Sun . X. J . Chung . Y. W . Cai . Z. M . Jiang . W. G . Chan . H. C . 10.1016/j.bbamcr.2013.07.021 . free .
  305. 22797075 . 2013 . Xie . C . CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer . Oncogene . 32 . 18 . 2282–2291, 2291.e1–7 . Jiang . X. H . Zhang . J. T . Sun . T. T . Dong . J. D . Sanders . A. J . Diao . R. Y . Wang . Y . Fok . K. L . Tsang . L. L . Yu . M. K . Zhang . X. H . Chung . Y. W . Ye . L . Zhao . M. Y . Guo . J. H . Xiao . Z. J . Lan . H. Y . Ng . C. F . Lau . K. M . Cai . Z. M . Jiang . W. G . Chan . H. C. . 3 . 10.1038/onc.2012.251 . 21255355 .
  306. 21866551 . 2012 . Sirnes . S. . Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome . International Journal of Cancer . 131 . 3 . 570–581 . Bruun . J. . Kolberg . M. . Kjenseth . A. . Lind . G. E. . Svindland . A. . Brech . A. . Nesbakken . A. . Lothe . R. A. . Leithe . E. . Rivedal . E. . 3 . 10.1002/ijc.26392 . 6293505 .
  307. 25422049 . 4306270 . 2015 . Schickling . B. M . BKCa channel inhibitor modulates the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway . Oncology Reports . 33 . 2 . 533–538 . England . S. K . Aykin-Burns . N . Norian . L. A . Leslie . K. K . Frieden-Korovkina . V. P. . 3 . 10.3892/or.2014.3617 .
  308. 7680475 . 45948 . 1993 . Felder . C. C. . Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx . Proceedings of the National Academy of Sciences of the United States of America . 90 . 5 . 1706–1710 . MacArthur . L . Ma . A. L . Gusovsky . F . Kohn . E. C. . 3 . 10.1073/pnas.90.5.1706. 1993PNAS...90.1706F . free .
  309. 27519272 . 4983040 . 2016 . Rezania . S . Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner . BMC Cancer . 16 . 628 . Kammerer . S . Li . C . Steinecker-Frohnwieser . B . Gorischek . A . Devaney . T. T . Verheyen . S . Passegger . C. A . Tabrizi-Wizsy . N. G . Hackl . H . Platzer . D . Zarnani . A. H . Malle . E . Jahn . S. W . Bauernhofer . T . Schreibmayer . W . 10.1186/s12885-016-2664-8 . free .
  310. 27835900 . 5356693 . 2016 . Kammerer . S . KCNJ3 is a new independent prognostic marker for estrogen receptor positive breast cancer patients . Oncotarget . 7 . 51 . 84705–84717 . Sokolowski . A . Hackl . H . Platzer . D . Jahn . S. W . El-Heliebi . A . Schwarzenbacher . D . Stiegelbauer . V . Pichler . M . Rezania . S . Fiegl . H . Peintinger . F . Regitnig . P . Hoefler . G . Schreibmayer . W . Bauernhofer . T. . 3 . 10.18632/oncotarget.13224.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Developmental bioelectricity".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.