Developmental bioelectricity
This article may contain an excessive number of citations. (November 2023) |
Developmental bioelectricity is the
Overview
Developmental bioelectricity is a sub-discipline of biology, related to, but distinct from,
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.[9][10] 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.[11][12]
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.[13] 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.[3][14][8][15][16] Bioelectric control mechanisms are an important emerging target for advances in regenerative medicine, birth defects, cancer, and synthetic bioengineering.[17][18]
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".[19][20][21] 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.[22][23] 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.[24][25][26] Du Bois-Reymond also reported in detail less fluctuating electricity at wounds – injury current and potential – he made to himself.[27][28]
Early 20th century
Developmental bioelectricity work began in earnest at the beginning of the 20th century.[30] Ida H. Hyde studied the role of electricity in the development of eggs.[31] T. H. Morgan and others studied the electrophysiology of the earthworm.[32] Oren E. Frazee studied the effects of electricity on limb regeneration in amphibians.[33] E. J. Lund explored morphogenesis in flowering plants.[34] Libbie Hyman studied vertebrate and invertebrate animals.[35][36]
In the 1920s and 1930s, Elmer J. Lund[37] and Harold Saxton Burr[38] wrote multiple papers about the role of electricity in embryonic development.[29] 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,[39][40] 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.[41][42][43][44][45]
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.[46] [47] [23][48]
C.D. Cone studied the role of resting potential in regulating cell differentiation and proliferation.[49][50] 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.[51]
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.[15]
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
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.[56][57] 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.[58]
The vibrating probe was introduced in biological studies in the 1970s.[59][60][41] 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.[41][61][62]
The vibrating ion-selective microelectrode was first used in 1990 to measure calcium fluxes in various cells and tissues.[63] 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.[61][64]
Emerging optic-based techniques,[65] 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[66] 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.[67] 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.[68]
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[70][71][72][73][74][75][excessive citations] and extracellular current measurements, facilitated by sophisticated self-referencing electrode systems.[76][77] While electrode applications for manipulating neuraly-controlled body processes have recently attracted much attention,[78][79] 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.[80] These include:
- Pharmacological screens to identify endogenous channels and pumps responsible for specific patterning events;[81][82][83]
- Voltage-sensitive fluorescent reporter dyes and genetically encoded fluorescent voltage indicators for the characterization of the bioelectric state in vivo.[84][85][86][87][88]
- Panels of well-characterized dominant ion channels that can be misexpressed in cells of interest to alter the bioelectric state in desired ways;[83][89][90] and
- Computational platforms that are coming on-line[91][92] to assist in building predictive models of bioelectric dynamics in tissues.[93][94][95]
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.[96]
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,[97][98] face,[99][100] eye,[89] brain,[101][102] and other organs. Screens have identified roles for ion channels in size control of structures such as the zebrafish fin,[103] 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.[89] 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.[102] and the control of tumorigenesis at the site of oncogene expression by bioelectric state of remote cells.[104][105]
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
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.[120][121] 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.[122][123][124][125][126][excessive citations] 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.
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).[134][135] 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.[131][132][136]
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.[137][138][139][140] 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.[141][142][143][144] Large sheets of monolayer epithelial cells, and sheets of stratified multilayered epithelial cells also migrate directionally.[132][145] 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.[146][147][148][149][150][151][152][excessive citations]
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.[153] 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.[154] 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.[127][155][156][12]
Following up on the relative success of electric stimulation on non-permissive frog leg regeneration using an implanted bimetallic rod in the late 1960s,[157] 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.[41][158] 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.[60][159][158][160] These studies in amphibian limb regeneration and related studies in lampreys and mammals [161] combined with those of bone fracture healing[162][163] and in vitro studies,[132] 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.[162][160][164] 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[165][166] and continued efforts at electrical stimulation.[167]
Recent molecular work has identified proton and sodium flux as being important for tail regeneration in Xenopus tadpoles,[12][168][169] 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,[170] pharmacological,[171] or optogenetic[172] methods. In planaria, work on bioelectric mechanism has revealed control of stem cell behavior,[173] size control during remodeling,[174] anterior-posterior polarity,[175] and head shape.[69][176] 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.[177][178][179] 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.[180]
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.[181][182] Indeed, it has long been known that gap junctions have a key role in carcinogenesis and progression.[183][184][185] Channels can behave as oncogenes and are thus suitable as novel drug targets.[3][93][183][186][187][188][189][190][191][192][excessive citations] Recent work in amphibian models has shown that depolarization of resting potential can trigger metastatic behavior in normal cells,[193][194] while hyperpolarization (induced by ion channel misexpression, drugs, or light) can suppress tumorigenesis induced by expression of human oncogenes.[195] Depolarization of resting potential appears to be a bioelectric signature by which incipient tumor sites can be detected non-invasively.[196] Refinement of the bioelectric signature of cancer in biomedical contexts, as a diagnostic modality, is one of the possible applications of this field.[181] 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.[195]
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[197][198][199][200][201][202][excessive citations] but also large-scale patterning.[29][203][204] 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).[205] 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,[179] the shape of the face in frog development,[99] and the size of tails in zebrafish.[103] Experimental modulation of endogenous bioelectric prepatterns have enabled converting body regions (such as the gut) to a complete eye,[89] inducing regeneration of appendages such as tadpole tails at non-regenerative contexts,[172][171][170] and conversion of flatworm head shapes and contents to patterns appropriate to other species of flatworms, despite a normal genome.[176] 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.[90][101]
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.
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.[101][104][105] Such non-cell-autonomous events suggest distributed network models of bioelectric control;[217][218][219] 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[218][220][69] 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,[166][165] and ion channel-modifying drugs (a kind of electroceutical) for repair of birth defects[90] and regenerative repair.[171] Synthetic biologists are likewise starting to incorporate bioelectric circuits into hybrid constructs.[221]
Table 1: Ion Channels and Pumps Implicated in Patterning
Protein | Morphogenetic role or LOF (loss of function) phenotype | Species | Reference |
---|---|---|---|
TRH1 K+ transporter | Root hair patterning | Arabidopsis | [222] |
Kir2.1potassium channel | Wing patterning | Drosophila | [223] |
Kir7.1 K+ channel | Craniofacial patterning, lung development | Mus musculus | [224] |
NHE2 Na+/H+ exchanger | Epithelial patterning | Drosophila | [225] |
V-ATPase proton pump | Wing hair patterning, Pigmentation and brain patterning, Craniofacial patterning | Drosophila, Oryzias latipes, Homo sapiens | [226][227][228] |
HCN1, Kv3.1 K+ channels | Forebrain patterning | Mus musculus | [229][230] |
KCNC1 K+ channel | Growth deficits | Mus musculus | [231] |
TWIK-1 K+ channel (KCNK1) | Cardiac (atrial) size | Mus musculus | [232] |
KCNJ6 K+channel | Keppen-Lubinsky syndrome – craniofacial and brain | Homo sapiens | [108] |
KCNH1 (hEAG1) K+ channel and ATP6V1B2 V-ATPase proton pump | Zimmermman-Laband and Temple-Baraitser syndrome – craniofacial and brain defects, dysplasia/aplasia of nails of thumb and great toe. | Homo sapiens | [116][233] |
GLRa4 chloride channel | Craniofacial anomalies | Homo sapiens | [234] |
KCNJ8 K+ | Cantu syndrome – face, heart, skeleton, brain defects | Homo sapiens | [235][236][237] |
NALCN (Na+ leak channel) | Freeman-Sheldon syndrome – limbs, face, brain | Homo sapiens | [238] |
CFTR chloride channel | Bilateral absence of vas deferens | Homo sapiens | [239][240] |
KCNC1 | Head/face dysmorphias | Homo sapiens | [241] |
KCNK9, TASK3 K+ channels | Birk-Barel Dysmorphism Syndrome – craniofacial defects, brain (cortical patterning) defects | Homo sapiens | [242][243][244] |
Kir6.2 K+ channel | Craniofacial defects | Homo sapiens | [244] |
KCNQ1 K+ channel (via epigenetic regulation) | Hypertrophy of tongue, liver, spleen, pancreas, kidneys, adrenals, genitalia – Beckwith-Wiedemann syndrome; craniofacial and limb defects, early development | Homo sapiens, Mus musculus, Drosophila | [245][246][247][248] |
KCNQ1 K+ channel | Jervell and Lange-Nielsen syndrome - inner ear and limb | Homo sapiens, Mus musculus | [249][250][251] |
Kir2.1 K+ channel (KNCJ2) | Andersen-Tawil syndrome – craniofacial, limb, ribs | Homo sapiens, Mus musculus | [106][223][252] |
GABA-A receptor (chloride channel) | Angelman Syndrome - craniofacial (e.g., cleft palate) and hand patterning | Homo sapiens, Mus musculus | [253][254][255] |
TMEM16A chloride channel | Tracheal morphogenesis | Mus musculus | [256] |
Girk2 K+ channel | Cerebellar development defects | Mus musculus | [257][258][259][260] |
KCNH2 K+ channel | Cardiac, craniofacial patterning defects | Mus musculus | [261] |
KCNQ1 K+ channel | Abnormalities of rectum, pancreas, and stomach | Mus musculus | [262] |
NaV1.2 | Muscle and nerve repair defects | Xenopus | [171] |
Kir6.1 K+ channel | Eye patterning defects | Xenopus | [89] |
V-ATPase ion pump | Left-right asymmetry defects, muscle and nerve repair | Xenopus, Gallus gallus domesticus, Danio rerio | [170][82] |
H,K-ATPase ion pump | Left-right asymmetry defects | Xenopus, Echinoidea | [263][264][265] |
Kir7.1 K+ channel | Melanosome development defects | Danio rerio | [266] |
Kv channels | Fin size regulation, heart size regulation | Danio rerio, Mus musculus | [103][267] |
NaV 1.5, Na+/K+-ATPase | Cardiac morphogenesis | Danio rerio | [268][269] |
KCNC3 | Dominant mutations cause cerebellar displasia in humans, and wing venation and eye defects in Drosophila. | Homo sapiens, Drosophila | [270] |
Table 2: Gap Junctions Implicated in Patterning
Gap Junction Protein | Morphogenetic role or LOF phenotype | Species | References |
---|---|---|---|
Innexins | Gonad and germline morphogenesis | C. Elegans | [271] |
Innexin1,2 | Cuticle (epithelial) patterning, foregut development | Drosophila | [272][273] |
Innexin 2 | Eye size | Drosophila | [274] |
Cx43 | Oculodentodigital dysplasia (ODDD), heart defects (outflow tract and conotruncal), left-right asymmetry randomization, Osteoblast differentiation problems, craniofacial defects, myogenesis | Homo sapiens, Mus musculus, Gallus gallus domesticus | [275][276][277][278][279][280][281][282][283][284][excessive citations] |
Cx37 | Lymphatic system patterning | Mus musculus | [285][286] |
Cx45 | Cardiac defects (cushion patterning) | Mus musculus | [287][288] |
Cx50, Cx46 | Eye defects (differentiation and proliferation problems, especially lens), | Mus musculus | [289] |
Cx26 | Cochlear development defects | Mus musculus | [290] |
Cx41.8 | Pigmentation pattern defects | Danio rerio | [291] |
Cx43 | Fin size and pattern regulation Craniofrontonasal syndrome |
Danio rerio, Mus musculus | [292][293][294][295] |
Inx4,Inx2 | Germline differentiation and spermatogenesis | Drosophila | [296] |
Pannexin3 | Skeletal development | Mus musculus | [297] |
Table 3: Ion Channel Oncogenes
Protein | Species | References | Cancer-role |
---|---|---|---|
NaV 1.5 channel | Homo sapiens | [298][299] | Oncogene |
ERG potassium channels | Homo sapiens | [300][301] | Oncogene |
9 potassium channel | Mus musculus | [302] | Oncogene |
Ductin (proton V-ATPase component) | Mus musculus | [303] | Oncogene |
SLC5A8 sodium/butyrate transporter | Homo sapiens | [304] | Oncogene |
KCNE2 potassium channel | Mus musculus | [305] | Oncogene |
KCNQ1 potassium channel | Homo sapiens, mouse | [246][262][306] | Oncogene |
SCN5A voltage-gated sodium channel | Homo sapiens | [299] | Oncogene |
Metabotropic glutamate receptor | Mus musculus, Human | [307][308] | Oncogene |
CFTR chloride channel | Homo sapiens | [309][310] | Tumor suppressor |
Connexin43 | Homo sapiens | [311] | Tumor suppressor |
BKCa | Homo sapiens | [312] | Oncogene |
Muscarinic Acetylcholine receptor | Homo sapiens, Mus musculus | [313] | Tumor suppressor |
KCNJ3 (Girk) | Homo sapiens | [314][315] | Oncogene |
References
- PMID 22050517.
- PMID 25425556.
- ^ PMID 26566112.
- ^ PMID 24773017.
- PMID 19167986.
- S2CID 10705650.
- ^ PMID 22020127.
- ^ PMID 28855098.
- PMID 20108228.
- PMID 23260134.
- ^ S2CID 7313742.
- ^ PMID 27827821.
- ^ Robinson, K.; Messerli, M. (1996). "Electric Embryos: the embryonic epithelium as a generator of development information". In McCaig, C (ed.). Nerve growth and guidance. Portland. pp. 131–141.
- PMID 29291972.
- ^ PMID 28633567.
- ^ Pitcairn, Emily; McLaughlin, Kelly A. (2016). "Bioelectric signaling coordinates patterning decisions during embryogenesis". Trends in Developmental Biology. 9: 1–9.
- ^ Pullar, C. E. The physiology of bioelectricity in development, tissue regeneration, and cancer., (CRC Press, 1996).[page needed]
- PMID 14711011.
- OCLC 13456516.
- OCLC 889251161.
- )
- ^ Maden, M. A history of regeneration research. (Cambridge University Press, 1991).[page needed]
- ^ PMID 15987799.
- S2CID 32435163.
- .
- S2CID 53175297.
- ^ Du Bois-Reymond, Emil (1860). Untersuchungen uber thierische Elektricitat [Investigations on Animal Electricity] (in German). Berlin: Georg Reimer.[page needed]
- OCLC 864592470.
- ^ PMID 22809139.
- .
- .
- .
- .
- .
- ISBN 978-0-226-87013-7.
- PMID 17795612.
- ^ Lund, E. Bioelectric fiends and growth, (University of Texas Press, 1947).[page needed]
- S2CID 84480134.
- ^ Marsh, G.; Beams, H. W. (1949). "Electrical control of axial polarity in a regenerating annelid". Anatomical Record. 105 (3): 513–514.
- PMID 20342775.
- ^ PMID 4421919.
- ISBN 978-0-8451-1501-5.
- PMID 6117911.
- ISBN 978-0-8412-3135-1.
- PMID 326151.
- PMID 3960913.
- PMID 6749746.
- S2CID 7534545.
- PMID 5148061.
- PMID 4518935.
- PMID 2443763.
- S2CID 4104520.
- PMID 24671205.
- ISBN 978-3-540-32717-2.
- PMID 27283241.
- S2CID 4104520.
- S2CID 45361295.
- S2CID 53316098.
- PMID 314968.
- ^ PMID 301554.
- ^ ISBN 978-3-642-64202-9.
- ^ S2CID 15237787.
- PMID 2335563.
- PMID 25993490.
- PMID 22341329.
- PMID 19823237.
- S2CID 25924011.
- PMID 25242672.
- ^ PMID 27574538.
- S2CID 12107878.
- PMID 1367098.
- PMID 21574266.
- PMID 20367249.
- PMID 20656468.
- PMID 28556571.
- S2CID 25177705.
- PMID 21204387.
- S2CID 2260750.
- PMID 23579662.
- ^ PMID 25896279.
- PMID 17078061.
- ^ PMID 16554361.
- ^ PMID 22350846.
- PMID 22474653.
- PMID 22474652.
- PMID 6704395.
- PMID 27428174.
- PMID 21356693.
- ^ PMID 22159581.
- ^ PMID 29519998.
- PMID 27458581.
- PMID 28954851.
- ^ PMID 26841954.
- PMID 27731412.
- PMID 25622192.
- S2CID 5265189.
- PMID 28702127.
- PMID 28818840.
- ^ PMID 26864374.
- S2CID 205768092.
- ^ PMID 25762681.
- ^ PMID 26198142.
- ^ PMID 24453984.
- ^ PMID 25646081.
- ^ PMID 24830454.
- ^ S2CID 33899188.
- S2CID 17015195.
- ^ PMID 25620207.
- PMID 24334122.
- PMID 20831951.
- PMID 19959877.
- PMID 24145769.
- PMID 27282200.
- PMID 27267311.
- S2CID 14238362.
- ^ S2CID 12060592.
- S2CID 12063113.
- PMID 23646327.
- PMID 22838235.
- PMID 23690510.
- S2CID 15325633.
- PMID 22917484.
- PMID 20518610.
- PMID 17433919.
- PMID 996878.
- PMID 412416.
- ^ PMID 7065232.
- ^ PMID 14786543.
- PMID 1521590.
- PMID 1864462.
- ^ PMID 15746181.
- ^ S2CID 4391475.
- PMID 27283241.
- ^ Maurice, D. M. The permeability to sodium ions of the living rabbit's cornea. J Physiol 112, 367-391. Pubmed Central reference number: PMC1393020
- ^ Klyce, S. D. Electrical profiles in the corneal epithelium. J Physiol 226, 407-429. Pubmed Central reference number: PMC1331188
- PMID 15371524.
- PMID 18684937.
- PMID 23447677.
- PMID 23541731.
- PMID 25062359.
- PMID 3905820.
- PMID 8834804.
- PMID 8799828.
- S2CID 11731666.
- PMID 8977469.
- PMID 26449415.
- PMID 26012633.
- PMID 11683396.
- PMID 26580832.
- PMID 27427485.
- S2CID 31682478.
- PMID 28739955.
- ^ Maden, M. (1991). A history of regeneration research. Cambridge University.[page needed]
- PMID 14946235.
- PMID 6526168.
- PMID 5499129.
- S2CID 22547794.
- ^ PMID 8812127.
- PMID 270701.
- ^ .
- ^ McCaig, C. D. Electric Fields in Vertebrate Repair., (The Physiological Society, 1989).
- ^ S2CID 84676921.
- .
- ^ Bruce M. Carlson, M. D., Ph.D. Principles of Regenerative Biology. (Academic Press, 2007).[page needed]
- ^ PMID 27257960.
- ^ PMID 20708956.
- PMID 26678416.
- PMID 19733557.
- PMID 23802040.
- ^ PMID 17329365.
- ^ PMID 20881138.
- ^ PMID 23519324.
- PMID 17670787.
- PMID 23250205.
- PMID 21276941.
- ^ PMID 26610482.
- PMID 16243308.
- PMID 20026026.
- ^ PMID 28538159.
- PMID 27565761.
- ^ PMID 23196890.
- PMID 23882223.
- ^ S2CID 30844116.
- PMID 17425504.
- PMID 16507402.
- S2CID 28497543.
- PMID 25049269.
- PMID 27713296.
- PMID 24493753.
- PMID 24493741.
- PMID 23683551.
- PMID 22484465.
- PMID 20959630.
- PMID 18931301.
- ^ PMID 26988909.
- PMID 23471912.
- PMID 26869018.
- PMID 25722947.
- PMID 26198143.
- PMID 23764116.
- PMID 23738690.
- PMID 18216177.
- PMID 22237730.
- PMID 23897652.
- PMID 27265625.
- PMID 22933452.
- PMID 17498955.
- PMID 21068304.
- PMID 21692661.
- PMID 26740890.
- PMID 28826673.
- PMID 28003330.
- PMID 27461864.
- PMID 23552369.
- PMID 23039994.
- PMID 20192780.
- PMID 27807271.
- ^ PMID 26571046.
- PMID 25788538.
- PMID 24882814.
- .
- PMID 11158535.
- ^ PMID 22949619.
- PMID 26402555.
- PMID 19234454.
- S2CID 15407237.
- PMID 24225653.
- PMID 12566520.
- PMID 26216856.
- PMID 23821603.
- ^ Zheng, J. a. T., M. C. Handbook of ion channels. (CRC Press, 2015).[page needed]
- PMID 27103460.
- S2CID 52799681.
- PMID 27506666.
- S2CID 73121.
- PMID 24700710.
- PMID 24176758.
- PMID 25683120.
- PMID 16272798.
- PMID 16840743.
- PMID 28145425.
- S2CID 14790826.
- PMID 18678320.
- ^ PMID 15115830.
- PMID 11120752.
- ^ PMID 11751681.
- PMID 10710224.
- PMID 16267222.
- S2CID 1700736.
- PMID 15498462.
- PMID 9312006.
- PMID 14522976.
- S2CID 19397785.
- S2CID 26049392.
- PMID 9108119.
- PMID 18585372.
- S2CID 6553698.
- PMID 4509657.
- PMID 3528411.
- S2CID 23470275.
- PMID 18948620.
- ^ PMID 23975432.
- PMID 24671205.
- S2CID 2502945.
- PMID 15992548.
- PMID 17121467.
- PMID 27038296.)
{{cite journal}}
: CS1 maint: numeric names: authors list (link - PMID 20339120.
- PMID 14602677.
- PMID 28467418.
- PMID 25195067.
- PMID 15047872.
- PMID 11956317.
- PMID 26455410.
- PMID 16378922.
- S2CID 13345970.
- S2CID 189036.
- PMID 7892609.
- PMID 7715640.
- PMID 18424255.
- PMID 10518488.
- PMID 10079509.
- PMID 11076975.
- S2CID 33491307.
- PMID 21515254.
- PMID 26079578.
- PMID 10903175.
- PMID 11673050.
- S2CID 25744002.
- S2CID 207068577.
- PMID 16845369.
- PMID 15649473.
- PMID 16968134.
- PMID 19150347.
- PMID 18406403.
- PMID 26116660.
- S2CID 8219978.
- PMID 19835862.
- ^ PMID 20651255.
- PMID 25945833.
- PMID 23744352.
- PMID 12782791.
- PMID 9796696.
- PMID 16375929.
- PMID 20625512.
- S2CID 24715509.
- PMID 23085756.
- PMID 21681448.
- PMID 23916755.
- S2CID 21255355.
- S2CID 6293505.
- PMID 25422049.
- PMID 7680475.
- PMID 27519272.
- PMID 27835900.
External links
- Quotations related to Developmental bioelectricity at Wikiquote