Voltage-Gated Sodium Channels Are Required for Heart Development in Zebrafish

Chopra, Sameer; Stroud, Dina Myers; Watanabe, Hiroshi; Bennett, Jeffrey S.; Burns, C. Geoffrey; Wells, K. Sam; Yang, Tao; Zhong, Tao; Roden, Dan M.

doi:10.1161/circresaha.109.213132

Cited by 76 publications

(84 citation statements)

References 31 publications

(35 reference statements)

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“…In addition to the conduction findings, the prolongation of action potential duration and diminution of peak action potential upstroke velocities recapitulate the electrical phenotypes of less differentiated cardiomyocytes (Milan et al, 2009;Panakova et al, 2010). Such changes in action potential upstroke velocity probably represent an increased dependence of depolarization on calcium channel conductance and a reduced role for sodium channel conductance (Chopra et al, 2010;Milan et al, 2009;Panakova et al, 2010). Global myocardial surface conduction progressed towards normal velocities at 14 dpi and 30 dpi, with recovery observed at 45 dpi.…”

Section: Ultrastructural and Physiological De-differentiation In Soursupporting

confidence: 52%

The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion

et al. 2011

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SUMMARYNatural models of heart regeneration in lower vertebrates such as zebrafish are based on invasive surgeries causing mechanical injuries that are limited in size. Here, we created a genetic cell ablation model in zebrafish that facilitates inducible destruction of a high percentage of cardiomyocytes. Cell-specific depletion of over 60% of the ventricular myocardium triggered signs of cardiac failure that were not observed after partial ventricular resection, including reduced animal exercise tolerance and sudden death in the setting of stressors. Massive myocardial loss activated robust cellular and molecular responses by endocardial, immune, epicardial and vascular cells. Destroyed cardiomyocytes fully regenerated within several days, restoring cardiac anatomy, physiology and performance. Regenerated muscle originated from spared cardiomyocytes that acquired ultrastructural and electrophysiological characteristics of de-differentiation and underwent vigorous proliferation. Our study indicates that genetic depletion of cardiomyocytes, even at levels so extreme as to elicit signs of cardiac failure, can be reversed by natural regenerative capacity in lower vertebrates such as zebrafish.

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Section: Ultrastructural and Physiological De-differentiation In Soursupporting

confidence: 52%

The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion

et al. 2011

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“…Using a combination of fluorescent voltage-reporter dyes to characterize spatial V mem distributions and functional studies using targeted misexpression of well-characterized ion transporters to specifically modify those gradients in vivo, instructive signaling roles of transmembrane voltage gradients have been identified in embryogenesis and regeneration, adding to the list of such roles identified in classical work that utilized functional physiology [248,249]. A number of recent molecular studies using unbiased approaches in human syndromes and non-human model systems have identified a range of ion channels, gap junctions, and ion pumps in developmental and regenerative morphogenesis of the face, brain, heart, appendages, growth of the cerebellum [250][251][252][253][254][255][256][257][258] and many other structures [259][260][261][262][263][264][265][266][267][268][269][270][271]. These physiological states are ideal inputs for the computational analysis delineated in the next section.…”

Section: Spatio-temporal Gradients Of V Mem Are Instructive Cues Mainmentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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“…Indeed, a number of recent molecular studies using unbiased approaches have identified a range of ion channels, gap junctions, and ion pumps in: morphogenesis of the trachea [127], development of skin pigmentation pattern [128,129], regeneration of the zebrafish fin [130], development of mammalian face [131–139], growth of the cerebellum [140–143], and formation of the skeletal [144], cardiac [145,146], and urogenital [147,148] systems. Thus in addition to experiments directly studying bioelectricity in amphibian, avian, and planarian systems, data from genetic models such as Drosophila also identifies channels such as Kir2.1 as important regulators of Dpp signaling and wing patterning [137].…”

Section: Introductionmentioning

confidence: 99%

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

Chernet¹,

Levin²

2014

J Clin Exp Oncol

130

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Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells’ activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ target morphology stored in real-time patterns of ion flows is perceived or mis-perceived by cells. Mastery of somatic voltage gradients will lead to cancer normalization or rebooting strategies, such as those that occur in regenerating and embryonic organs, resulting in transformative advances in basic biology and oncology.

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Voltage-Gated Sodium Channels Are Required for Heart Development in Zebrafish

Cited by 76 publications

References 31 publications

The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion

The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

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