Guide Signaling in the Heart

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This brief review will give a general overview of some major intracellular signalling systems operative in cells comprising the heart and vasculature, with.
Table of contents

Dev Biol : — Cardiac expression of the ventricle-specific homeobox gene Irx4 is modulated by Nkx and dHand. Cardiomyopathy in Irx4-deficient mice is preceded by abnormal ventricular gene expression. Mol Cell Biol 21 : — A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.

Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6 : — Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5 : — Epigenetics and cardiovascular development. Annu Rev Physiol 74 : 41 — A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis.

BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development : — Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell 9 : — Chamber formation and morphogenesis in the developing mammalian heart.

Formation of the venous pole of the heart from an Nkxnegative precursor population requires Tbx The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. The T-box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. Nat Cell Biol 13 : — J Biol Chem : — MesP1 drives vertebrate cardiovascular differentiation through Dkkmediated blockade of Wnt-signalling.

Nat Cell Biol 10 : — Gene regulatory networks and the evolution of animal body plans. Science : — Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 44 : — Directed differentiation of human embryonic stem cells to interrogate the cardiac gene regulatory network. Mol Ther 19 : — Deletion of the selection cassette, but not cis -acting elements, in targeted Flk1-lacZ allele reveals Flk1 expression in multipotent mesodermal progenitors.

Blood : — Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 7 : — Google Scholar. Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1. Nat Genet 18 : — Left and right ventricular contributions to the formation of the interventricular septum in the mouse heart. Dev Biol 2 : — Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis.

Atrial myocardium derives from the posterior region of the second heart field, which acquires left-right identity as Pitx2c is expressed. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis.

Nat Genet 31 : 25 — Forcing cells to change lineages. Notch signaling is essential for ventricular chamber development. Dev Cell 12 : — Cooperative action of Tbx2 and Nkx2. Genes Dev 16 : — Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature : 62 — Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development.

Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci : — Polycomb repressive complex 2 regulates normal development of the mouse heart. Genes Dev 26 : 37 — Hinton RB Jr. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Sonic hedgehog is required in pulmonary endoderm for atrial septation. The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart.

Cardiovasc Res 62 : — Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev 21 : — Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13 : — Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.

Di George syndrome phenotype in mice mutant for the T-box gene. Tbx1 Nat Genet 27 : — CrossRef Google Scholar.

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Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Dev Cell 11 : — Cell Stem Cell 8 : — Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes. The arterial pole of the mouse heart forms from Fgfexpressing cells in pharyngeal mesoderm. Dev Cell 1 : — Co-activation of atrial natriuretic factor promoter by Tip60 and serum response factor.

The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. Reptilian heart development and the molecular basis of cardiac chamber evolution.

Nature : 95 — Kouzarides T Kouzarides T. Chromatin modifications and their function. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11 : — Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Nat Cell Biol 11 : — Regenerating the heart. Nat Biotechnol 23 : — Heart regeneration.

Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25 : — Islet1 cardiovascular progenitors: A single source for heart lineages? Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85 : — Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo.

Advanced cardiac morphogenesis does not require heart tube fusion. The role of chromatin during transcription. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. A chemical platform for improved induction of human iPSCs. Nat Meth 6 : — Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature : 97 — Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs.

Cell Stem Cell 3 : 55 — Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx Genes Dev 9 : — Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning.

Anterior visceral endoderm directs ventral morphogenesis and placement of head and heart via BMP2 expression. Dev Cell 21 : — Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner.

Curr Opin Genet Dev 11 : — A retrospective clonal analysis of the myocardium reveals two phases of clonal growth in the developing mouse heart. The clonal origin of myocardial cells in different regions of the embryonic mouse heart.

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Dev Cell 6 : — Oriented clonal cell growth in the developing mouse myocardium underlies cardiac morphogenesis. J Cell Biol : 97 — Multiple essential functions of neuregulin in development. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Molecular pathway for the localized formation of the sinoatrial node.

The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc Res 87 : 92 — Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Cardiac chamber formation: Development, genes, and evolution.

Physiol Rev 83 : — TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Curr Opin Cardiol 19 : — The T-Box transcription factor TBX5 is required for the patterning and maturation of the murine cardiac conduction system. A molecular pathway including id2, tbx5, and nkx required for cardiac conduction system development. An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation.

Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart. Gene regulatory networks in the evolution and development of the heart. Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Genes Dev 13 : — Transient regenerative potential of the neonatal mouse heart. Advances in understanding tissue regenerative capacity and mechanisms in animals.

Nat Rev Genet 11 : — Heart regeneration in zebrafish. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Development of heart valves requires Gata4 expression in endothelial-derived cells. The promise of induced pluripotent stem cells in research and therapy. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Congenital heart disease caused by mutations in the transcription factor NKX Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.

The left-right axis in the mouse: From origin to morphology. Control of cardiac-specific transcription by p through myocyte enhancer factor-2D. De novo cardiomyocytes from within the activated adult heart after injury. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible cre protein. Circ Res 89 : 20 — Heart repair by reprogramming non-myocytes with cardiac transcription factors. Regionalized sequence of myocardial cell growth and proliferation characterizes early chamber formation. Circ Res 99 : — Srivastava D Srivastava D.

Making or breaking the heart: From lineage determination to morphogenesis. Nat Genet 16 : — Dev Cell 14 : — VEGF signaling has distinct spatiotemporal roles during heart valve development. BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium. Polycomb group proteins set the stage for early lineage commitment. Cell Stem Cell 7 : — Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors.

Chromatin remodeling complex dosage modulates transcription factor function in heart development. Nat Commun 2 : The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: The role of ingression and tissue movement during gastrulation.

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Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development. Medline Google Scholar. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18 : 99 — Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. Dev Cell 19 : — A caudal proliferating growth center contributes to both poles of the forming heart tube.

The sequence of the human genome. How to make a heart: The origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 90 : 1 — Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.

Cell 93 : — Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. A retinoic acid-inducible transgenic marker of sino-atrial development in the mouse heart. Tbx5-Hedgehog molecular networks are essential in the second heart field for atrial septation.

Dev Cell 23 : — Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development — A chemical approach to stem-cell biology and regenerative medicine. Nuclear reprogramming to a pluripotent state by three approaches. This induced an instantaneous acceleration of EB beating frequencies to a maximum of Because short and repetitive stimulations would be technically very challenging or even impossible using receptor agonists, our approach will enable experimental paradigms to explore the differential impact of long-lasting vs.

Histological sections of the heart showed cytosolic GFP expression and membrane-bound JellyOp signal in all ventricular cardiomyocytes Fig.

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JellyOp mice were viable and did not show any obvious phenotype. To exclude possible hypertrophic side effects, we determined the heart weight to femur length ratio and could not detect a difference between JellyOp and wild-type mice Fig. Ventricular cardiomyocytes were dissociated and investigated using patch-clamp and contraction measurements. Contractility and relaxation speed were analyzed by edge detection of isolated, electrically paced ventricular cardiomyocytes. Interestingly, maximal relaxation speed was reached JellyOp function in isolated mouse ventricular cardiomyocytes.

To modulate chronotropy of the heart, we investigated the atria of JellyOp mice and found bright GFP fluorescence and membrane-bound JellyOp signals in atrial cardiomyocytes Fig. Illumination 2. The ability of JellyOp to modulate the beating rate was analyzed in explanted, Langendorff-perfused hearts. After reaching the peak frequency, hearts showed a clear reduction of the chronotropic response during illumination with a time constant of Importantly, the chronotropic effect returned almost instantaneously to baseline after termination of illumination in contrast to a sustained effect after wash out of isoprenaline Fig.

This data and the fit Eq. However, we would like to point out that light penetration into the tissue surrounding the sinus node is wavelength dependent and light can be toxic at high intensities e. JellyOp function in mouse atria of intact hearts. This led to an almost instantaneous acceleration of the spontaneous sinus rhythm by Importantly, the very short delay from light to rate response correlates well with recent reports using optogenetic stimulation of cardiac sympathetic neurons 20 , Spatial difference of JellyOp stimulation in the left and right atria.

Insert red box highlights the short delay between light blue bar and start of heart rate acceleration. It is known that atrial premature contractions inducing atrial fibrillation are often originating from the ostia of pulmonary veins in the dorsal left atrium 22 , This initially induced a mild acceleration of sinus rhythm possibly due to scattered light to the sinus node , which was subsequently interposed by spontaneous premature atrial contractions Fig.

These were characterized by premature P-waves with different morphology compared to regular sinus rhythm Fig. Importantly, we have not observed such premature atrial contractions when flashing light with identical parameters on the right atrium of JellyOp mice. Because of the lack of cell-type specific expression of JellyOp, definitive conclusions on the mechanism and the cell types involved in the observed supraventricular arrhythmia cannot be drawn at this stage. Taken together, we herein present JellyOp as an optogenetic tool to investigate G s -signaling in the heart.

The precise spatial and temporal control allows novel stimulation protocols to determine the physiological and pathophysiological effects of G s -activation for pacemaker function and arrhythmia generation in the intact heart. As a proof-of-concept, we have investigated the precise temporal delay between activation of the receptor and downstream effects on pacemaker activity and contractility in vitro as well as in the intact heart and demonstrated spatial differences of G s -signaling in the left and right atria. Importantly, we could not detect any side effects on the heart by overexpressing JellyOp indicating a lack of adverse dark activity.

At this stage, we cannot exclude that JellyOp slightly also activates G i -proteins, and thereby impairs the G s effect. In general, direct optogenetic stimulation of G-protein coupled receptors will provide new insights into temporal and spatial aspects of G-protein and downstream signaling, and the consequences for cardiovascular patho- physiology.

The plasmid was confirmed by sequencing and linearized with BglII before transfection. G4 hybrid ESCs mycoplasma negative, kindly provided by A. Nagy and M. GFP positive clones were picked and further propagated. During ESC culture, 9-Cis retinal was not supplemented. ESCs were differentiated within EBs using the hanging drop method 20, cells per drop 7 , After 2 days, hanging drops were washed and kept in suspension on a horizontal shaker for 3 days.

At day 5 of differentiation, EBs were either plated on 0. For a detailed analysis of light sensitivity of cAMP production Fig. The following 5 days, cells were kept in high-lactate IMDM and on day 20, purified cardiomyocytes were dissociated for a second time and cells were plated per well of a 24 multiwell plate.

Light stimulation 2. EBs were plated at day 5 of differentiation on 0. Thirty minutes before the experiment, medium was replaced by Tyrode solution in mM: NaCl, 5. Light intensity was determined at the objective with a power meter and appropriate wavelength correction PM powermeter and SA sensor, Thorlabs. Spontaneous beating was recorded with a CCD camera piAgm, Basler at 51 frames per second and analyzed online using custom-designed software LabView, National Instruments as described before 7. To reduce experimental noise from single arrhythmic contractions, the raw frequency response to each light pulse was fitted with an Asym2Sig fit formula Origin 8, OriginLab.

Time constants for inactivation from peak to plateau frequency and for deactivation from peak to baseline frequency were determined by an exponential decay fit ExpDec1, Origin 8. Transgenic mice were generated by aggregation of JellyOp expressing, transgenic G4 ESCs with 40 chromosome karyotype and diploid morula stage CD-1 embryos as described previously Chimeric mice, as identified by their coat color chimerism, were bred to CD-1 mice to test germline transmission.

Offspring with agouti coat color were analyzed for inheritance of the transgene by detection of GFP signal in tail tissue. Dry heart weight was normalized to the femur length.

Ventricular cardiomyocytes were isolated from JellyOp mice, as described previously Single cells were plated at low density on laminin-coated 0. Patch-clamp experiments were performed using an EPC10 amplifier Heka in the whole cell configuration. Contractions of single cardiomyocytes were recorded with an edge detection system Myocam S and IonWizard software, Ionoptix. The average cell shortening of 11 contractions before illumination was compared with the average cell shortening of 11 beats around the maximal peak of cell shortening.

Mice were heparinized and sacrificed by cervical dislocation. Hearts were explanted and perfused in Langendorff configuration with Tyrode solution. The spatial extent of the illumination was varied using the zoom function of the macroscope.

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To determine maximal frequency increase during light stimulation Fig. Spectral sensitivity of JellyOp Fig. To analyze light sensitivity Fig. For induction of supraventricular extra beats Fig. After permeabilization with 0. Fluorescence images of histological sections were acquired with an inverted microscope equipped with an optical section module Axiovert with ApoTome and AxioVision 4. Statistics were performed with GraphPad Prism 8. Introduction The heart is the first organ to form and function during vertebrate development.

Download: PPT. Fig 1. Fig 2. Myocardial Rbpj deletion does not affect ventricular development and structure. Fig 3. Expression pattern of compact and trabecular myocardium markers, NOTCH target genes, and fibrosis marker staining is normal in Rbpj flox ;Tnnt2-Cre embryos, while Vegf is not significantly increased. Fig 4. Table 1. Myocardium-specific Rbpj flox mutants are viable and reach adulthood. Fig 5. Table 2.

Quantification of Rbpj deletion Rbpj immunostaining was analyzed using ImageJ software. Ultrasound Left ventricle LV function and mass were analyzed by transthoracic echocardiography in 6 months of age mice. Electrocardiograms Electrocardiograms were recorded with and MP36 system and analyzed using the Acknowledge 4 software. Statistical analysis Statistical analysis was carried out using Prism 7 GraphPad. Supporting information. S1 Table. Fig 2C quantitative data. S2 Table. Fig 4E and 4F quantitative data. S3 Table. Fig 4G quantitative data. S4 Table. Fig 5G quantitative data.

S5 Table. Genotyping primers list. References 1. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol. Notch signaling is essential for ventricular chamber development. Dev Cell. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Benedito R, Hellstrom M.

Notch as a hub for signaling in angiogenesis. Exp Cell Res. Gridley T. Notch signaling in vascular development and physiology. Circ Res. Notch signaling at a glance. J Cell Sci. Kopan R, Ilagan MX.

The canonical Notch signaling pathway: unfolding the activation mechanism. Signalling downstream of activated mammalian Notch Nature. Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol. Hey bHLH transcription factors. Sequential Notch activation regulates ventricular chamber development.

Nature cell biology. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis.

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Recombination signal sequence-binding protein Jkappa alters mesodermal cell fate decisions by suppressing cardiomyogenesis. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Notch1 is essential for postimplantation development in mice. View Article Google Scholar Developmental patterning of the myocardium. Anat Rec. Monitoring Notch1 activity in development: Evidence for a feedback regulatory loop. Dev Dyn. Nat Med. FEBS J. Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium.

Cell Rep. Coordinating tissue interactions: notch signaling in cardiac development and disease.