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PubMed2000

Presence of functional sarcoplasmic reticulum in the developing heart and its confinement to chamber myocardium.

During development fast-contracting atrial and ventricular chambers develop from a peristaltic-contracting heart tube. This study addresses the question of whether chamber formation is paralleled by a matching expression of the sarcoplasmic reticulum (SR) Ca(2+) pump. We studied indo-1 Ca(2+) transients elicited by field stimulation of linear heart tube stages and of explants from atria and outflow tracts of the prototypical preseptational E13 rat heart. Ca(2+) transients of H/H 11+ chicken hearts, which constitute the prototypic linear heart tube stage, were sensitive to verapamil only, indicating a minor contribution of Ca(2+)-triggered SR Ca(2+) release. Outflow tract transients displayed sensitivity to the inhibitors similar to that of the linear heart tube stages. Atrial Ca(2+) transients disappeared upon addition of ryanodine, tetracaine, or verapamil, indicating the presence of Ca(2+)-triggered SR Ca(2+) release. Quantitative radioactive in situ hybridization on sections of E13 rat hearts showed approximately 10-fold higher SERCA2a mRNA levels in the atria compared to nonmyocardial tissue and approximately 5-fold higher expression in compact ventricular myocardium. The myocardium of atrioventricular canal, outflow tract, inner curvature, and ventricular trabecules displayed weak expression. Immunohistochemistry on sections of rat and human embryos showed a similar pattern. The significance of these findings is threefold. (i) A functional SR is present long before birth. (ii) SR development is concomitant with cardiac chamber development, explaining regional differences in cardiac function. (iii) The pattern of SERCA2a expression underscores a manner of chamber development by differentiation at the outer curvature, rather than by segmentation of the linear heart tube.

Animals↗
PubMed1999

Cell death in the endocardial cushions of the developing heart.

The incidence of apoptotic cells in the hearts of chick embryos between days 4 and 8 of development was examined using an in situ technique for the detection of DNA fragmentation. Using this method it was possible to demonstrate foci of apoptotic cells primarily in two locations: the outflow tract cushions and the atrioventricular cushions. Both occurred only during narrow time windows: between embryonic days 4.5 and 6.5 in the outflow tract, and between embryonic days 5.5 and 7.5 in the atrioventricular canal. This is a much more restricted distribution of dying cells than previously thought, with reproducible cell death notably absent from the atrial and ventricular walls. Dying cells were also unexpectedly absent from the fusion seam of apposed cushions. In a complementary study, cell proliferation in these tissues was examined over the same time period using the expression of proliferating cell nuclear antigen as a marker for dividing cells. Cell proliferation occurred throughout the region of the cushions at these stages, including the myocardium and the fusion points of the apposed cushions. It is concluded that cells undergoing programmed cell death at this time in the developing chick heart are abundant in, and largely restricted to, the cushion tissue, and that cushion morphogenesis is regulated by the co-ordination of cell transformation, cell proliferation and, during a narrow time window, cell death.

Animals↗
PubMed1980

Immunofluorescence studies for myosin, alpha-actinin and tropomyosin in developing hearts of normal and cardiac lethal mutant Mexican axolotls, Ambystoma mexicanum.

Recessive mutant gene c in axolotl embryos results in an absence of normal heart function. Immunofluorescence studies were done to determine the distributions of myosin, tropomyosin and alpha-actinin in the hearts of normal and mutant siblings. Anti-myosin specifically stains the A bands of myofibrils in normal hearts and reveals a progressive increase in myofibril organization with development. Mutant hearts display less staining for myosin than normal and localization is mainly in amorphous collections. Anti-alpha-actinin stains the Z lines of myofibrils in normal myocytes. Mutant cells also have significant staining for alpha-actinin but show no striations. Antitropomyosin intensely stains the I bands of myofibrils in normal cells; however, there is very little staining for tropomyosin in mutant hearts. Thus, mutant myocardial cells have reduced but significant amounts of actin (Lemanski, Mooseker, Peachey & Iyengar, 1976) and myosin, even though non-filamentous, and substantial amounts of alpha-actinin. The cells appear to contain little tropomyosin.

Actinin↗
PubMedDate not supplied

Correlations between protein kinase C zeta signaling and morphological modifications during rat heart development and aging.

From birth to aging the heart undergoes functional changes reflecting biochemical and ultrastructural modifications which imply apoptosis. This is a physiological process resulting from genetic programs closely associated with development and aging. During development apoptosis eliminates redundant cells leading to heart remodeling, while during aging it eliminates damaged or exhausted cells. In the present paper we analyze some molecular mechanisms involved with heart morphological modifications, especially in the neonatal heart which displays different features in the subendocardial and myocardial area. The high number of subendocardial apoptotic cells and the inverted ratio of Bcl-2/Bax molecule expression in the two heart compartments led us to hypothesize a different metabolism in the myocardium as compared with subendocardium. Moreover, we propose that PKC zeta may mediate this different response by activating Nf-kB pathway and by maintaining the balance between hypertrophic growth and apoptosis involved with remodeling of neonatal heart. Further, we underline that in the aged heart, where this pathway is not activated, such balance is not maintained.

Aging↗
PubMed1991

Optical approaches to ontogeny of electrical activity and related functional organization during early heart development.

Direct intracellular measurement of electrical events in the early embryonic heart is impossible because the cells are too small and frail to be impaled with microelectrodes; it is also not possible to apply conventional electrophysiological techniques to the early embryonic heart. For these reasons, complete understanding of the ontogeny of electrical activity and related physiological functions of the heart during early development has been hampered. Optical signals from voltage-sensitive dyes have provided a new powerful tool for monitoring changes in transmembrane voltage in a wide variety of living preparations. With this technique it is possible to make optical recordings from the cells that are inaccessible to microelectrodes. An additional advantage of the optical method for recording membrane potential activity is that electrical activity can be monitored simultaneously from many sites in a preparation. Thus, applying a multiple-site optical recording method with a 100- or 144-element photodiode array and voltage-sensitive dyes, we have been able to monitor, for the first time, spontaneous electrical activity in prefused cardiac primordia in the early chick embryos at the six- and the early seven-somite stages of development. We were able to determine that the time of initiation of the contraction is the middle period of the nine-somite stage. In the rat embryonic heart, the onset of spontaneous electrical activity and contraction occurs at the three-somite stage. In this review, a new view of the ontogenetic sequence of spontaneous electrical activity and related physiological functions such as ionic properties, pacemaker function, conduction, and characteristics of excitation-contraction coupling in the early embryonic heart are discussed.

Animals↗
PubMed2004

Modulation of eomes activity alters the size of the developing heart: implications for in utero cardiac gene therapy.

Congenital heart disease is the most prevalent cause of infant morbidity and mortality in developed countries. The mechanisms responsible for many specific types of congenital cardiac malformations are strongly associated with gene abnormalities. However, at this time no strategies for gene therapy of the various congenital heart malformations have been investigated. In the present studies we focus on Eomesodermin (Eomes), a T-box transcription factor expressed in developing vertebrate mesoderm. Although Eomes is required for early mesodermal patterning and differentiation, the role of Eomes in cardiac development is unknown. In the present studies we demonstrate that Eomes is expressed in the developing heart, with a pronounced myocardial distribution in the Xenopus ventricle during late cardiac development. Using either a conditional dominant-interfering approach (GR-Eomes--engrailed) or an Eomes-activating approach (GR-Eomes-VP16) we demonstrate that manipulating Eomes activity during late cardiac development can either suppress ventricular development (GR-Eomes-enR) or increase ventricular myocardial size (GR-Eomes-VP16). Thus, a potential gene therapy approach for treating both congenital ventricular hypoplasia (e.g., the hypoplastic left heart syndrome) and hypertrophic cardiomyopathy is hypothetically implicit from the present results.

Animals↗
PubMed1995

Cardiac myosin heavy chain expression during heart development in Xenopus laevis.

Muscle-specific gene expression in the heart during Xenopus development was investigated using reverse transcription-polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization to detect transcripts of the gene for the cardiac myosin heavy chain (CMHC). RT-PCR analysis determined that CMHC transcripts are present in the cardiac mesoderm at state 13, demonstrating that muscle-specific gene expression in the primitive myocardium has begun by the early neurula stage, approximately 30 h before the heart beat begins. Xenopus, therefore, is similar to amniotes and mammals in that cardiac precursor cells begin to express muscle-specific gene transcripts soon after commitment to the cardiac myocyte lineage. The earliest CMHC gene transcripts can be detected in the heart using whole-mount in situ hybridization is early tailbud stage 28, which coincides with the onset of heart tube morphogenesis. CMHC gene expression was also detected in skeletal muscle: RT-PCR analysis determined that CMHC transcripts are transiently expressed in the somite during the initial phases of skeletal muscle differentiation. Furthermore, CMHC mRNAs are expressed in a subset of head muscles of the feeding tadpole. CMHC gene expression is induced in ectodermal cells of the animal cap in blastula-stage embryos injected with synthetic MyoD or Myf5 RNA, suggesting that the CMHC gene contains regulatory elements that are responsive to the activity of those skeletal-muscle-specific transcription factors.

Amino Acid Sequence↗
PubMed1995

The extracellular matrix during heart development.

The embryonic extracellular matrix, which is comprised of glycosaminoglycans, glycoproteins, collagens, and proteoglycans, is believed to play multiple roles during heart morphogenesis. Some of these ECM components appear throughout development, however, certain molecules exhibit an interesting transient spatial and temporal distribution. Due to significant new data that have been gathered predominantly in the past 10 years, a comprehensive review of the literature is needed. The intent of this review is to highlight work that addresses mechanisms by which extracellular matrix influences vertebrate heart development.

Animals↗
PubMed1998

Cre-loxP-mediated inactivation of the alpha6A integrin splice variant in vivo: evidence for a specific functional role of alpha6A in lymphocyte migration but not in heart development.

Two splice variants of the alpha6 integrin subunit, alpha6A and alpha6B, with different cytoplasmic domains, have previously been described. While alpha6B is expressed throughout the development of the mouse, the expression of alpha6A begins at 8.5 days post coitum and is initially restricted to the myocardium. Later in ontogeny, alpha6A is found in various epithelia and in certain cells of the immune system. In this study, we have investigated the function of alpha6A in vivo by generating knockout mice deficient for this splice variant. The Cre- loxP system of the bacteriophage P1 was used to specifically remove the exon encoding the cytoplasmic domain of alpha6A in embryonic stem cells, and the deletion resulted in the expression of alpha6B in all tissues that normally express alpha6A. We show that alpha6A-/- mice develop normally and are fertile. The substitution of alpha6A by alpha6B does not impair the development and function of the heart, hemidesmosome formation in the epidermis, or keratinocyte migration. Furthermore, T cells differentiated normally in alpha6A-/- mice. However, the substitution of alpha6A by alpha6B leads to a decrease in the migration of lymphocytes through laminin-coated Transwell filters and to a reduction of the number of T cells isolated from the peripheral and mesenteric lymph nodes. Lymphocyte homing to the lymph nodes, which involves various types of integrin-ligand interactions, was not affected in the alpha6A knockout mice, indicating that the reduced number of lymph node cells could not be directly attributed to defects in lymphocyte trafficking. Nevertheless, the expression of alpha6A might be necessary for optimal lymphocyte migration on laminin in certain pathological conditions.

Alternative Splicing↗
PubMed2001

Identification and characterization of Lbh, a novel conserved nuclear protein expressed during early limb and heart development.

We report the cloning, protein characterization, and expression of a novel vertebrate gene, termed Lbh (Limb-bud-and-heart), with a spatiotemporal expression pattern that marks embryologically significant domains in the developing limbs and heart. Lbh encodes a highly conserved nuclear protein, which in tissue culture cells possesses a transcriptional activator function. During limb development, expression of Lbh initiates in the ectoderm of the presumptive limb territory in the lateral body wall. As the limb buds appear, Lbh expression is restricted primarily to the distal ventral limb ectoderm and the apical ectodermal ridge, and overlaps in these ectodermal compartments with En1 and Fgf8 expression. During heart formation, Lbh is expressed as early as Nkx2.5 and dHand in the bilateral heart primordia, with the highest levels in the anterior promyocardium. After heart tube fusion and looping, Lbh expression is confined to the ventricular myocardium, with the highest intensity in the right ventricle and atrioventricular canal, as well as in the sinus venosus. Based on the molecular characteristics and the domain-specific expression pattern, it is possible that Lbh functions in synergy with other genes known to be required for heart and limb development.

Amino Acid Sequence↗
PubMed2005

Temporal and spatial expression pattern of beta1 sodium channel subunit during heart development.

OBJECTIVES: The aim of this study is to analyze Scn1b mRNA expression levels and protein distribution of Scn1b, a putative modulator of the pore-forming Na(+) channel subunit in the heart, during mouse cardiac development. METHODS: Scn1b mRNA levels were determined by real-time RT-PCR using embryonic hearts ranging from E9.5 to E18.5 as well as in postnatal and adult heart. Scn1b protein distribution and subcellular localization during cardiogenesis were analyzed by immunohistochemistry and confocal microscopy. RESULTS: Scn1b mRNA showed a dynamic expression pattern, peaking at stage E12.5 and decreasing at E15.5. Scn1b mRNA increased at later embryonic and neonatal stages, being maximal in the adult heart. Immunohistochemistry experiments revealed comparable distribution of Scn1b protein between the different cardiac chambers at early embryonic stages. With further development, Scn1b protein showed an enhanced expression in the trabeculated myocardium and the bundle branches. At the subcellular level in later embryonic and postnatal mouse cardiomyocytes, Scn1b was present in T-tubules as identified by immunostaining of alpha-actinin, and in the intercalated disks as identified by immunostaining of connexin 43. CONCLUSION: These results demonstrate that Scn1b is expressed during mouse heart development, suggesting it can play an important role in the action potential configuration of the cardiomyocytes during heart morphogenesis.

Aging↗
PubMed1992

Multiple connexins confer distinct regulatory and conductance properties of gap junctions in developing heart.

Multiple gap junction proteins (connexins) and channels have been identified in developing and adult heart. Functional expression of the three connexins found in chick heart (connexin42, connexin43, and connexin45) by stable transfection of communication-deficient neuro2A (N2A) cells revealed that all three connexin cDNAs are capable of forming physiologically distinct gap junctions that differ in their transjunctional voltage dependence and unitary channel conductances. The transjunctional voltage dependences of connexin45 and connexin42 closely resembled those of 4-day and 18-day embryonic chick heart gap junctions, respectively. The multiple channel conductances between 80 and 240 pS, including the predominant 160 pS channel, observed in embryonic chick heart were also common to connexin42. The expression of multiple gap junction channels with distinct conductance and regulatory properties within a given tissue may account for developmental changes in intercellular communication.

Animals↗
PubMed2001

Gene expression of SERCA2a and L- and T-type Ca channels during human heart development.

In this study we report, for the first time, on the gene expression of human cardiac SERCA2a, L-type (alpha(1C)) and T-type (alpha(1H)) Ca channels during development, using RNase protection assay, relative quantitative RT-PCR and Western blot. Human hearts during early gestation (8- to 20-wk gestation), neonatal (1- to 4-d-old) and adult (18- to 48-year-old) stages were used. The results show that T-type Ca channel alpha(1H) subunit mRNA decreased and that L-type Ca channel alpha(1C) subunit mRNA increased with development. While the levels of sarcoplasmic reticulum ATPase (SERCA2a) mRNA did not significantly change with development, its protein levels increased with development. In conclusion, SERCA2a, L-type and T-type Ca channel transcripts were detected as early as 8-wk gestation. Defining the profile of Ca handling proteins during development is important to the understanding of excitation-contraction (EC)-coupling of the developing human heart.

Adult↗
PubMed2000

Xenopus Hand2 expression marks anterior vascular progenitors but not the developing heart.

We have isolated cDNAs encoding the bHLH protein Hand2 in the amphibian Xenopus laevis and analysed Hand2 expression in early development from the onset of gastrulation to feeding tadpole stages. XHand2 is expressed in the branchial arch mesenchyme and also in small bilateral populations of cells in the anterior, ventrolateral region of early tailbud embryos. At later stages, these punctate Hand2-expressing cells are located at the sites of the forming common cardinal veins, suggesting that they may constitute progenitors of vascular smooth muscle cells. Other Hand2-expressing cells are also associated with further components of the forming anterior vasculature but are not detected in mature blood vessels. Interestingly, no myocardial expression of XHand2 can be detected in the developing tadpole heart, in marked contrast to results obtained with chick and mouse embryos.

Amino Acid Sequence↗
PubMed2005

Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart.

The arterial pole of the heart is the region where the ventricular myocardium continues as the vascular smooth muscle tunics of the aorta and pulmonary trunk. It has been shown that the arterial pole myocardium derives from the secondary heart field and the smooth muscle tunic of the aorta and pulmonary trunk derives from neural crest. However, this neural crest-derived smooth muscle does not extend to the arterial pole myocardium leaving a region at the base of the aorta and pulmonary trunk that is invested by vascular smooth muscle of unknown origin. Using tissue marking and vascular smooth muscle markers, we show that the secondary heart field, in addition to providing myocardium to the cardiac outflow tract, also generates prospective smooth muscle that forms the proximal walls of the aorta and pulmonary trunk. As a result, there are two seams in the arterial pole: first, the myocardial junction with secondary heart field-derived smooth muscle; second, the secondary heart field-derived smooth muscle with the neural crest-derived smooth muscle. Both of these seams are points where aortic dissection frequently occurs in Marfan's and other syndromes.

Animals↗
PubMed2006

Differential regulation of Tbx5 protein expression and sub-cellular localization during heart development.

The T-box transcription factor Tbx5 can interact with Nkx2.5 and Gata4 transcription factors to synergistically regulate heart-specific genes in the nucleus. While a nuclear role for Tbx5 is clearly defined, we have previously shown that Tbx5 shuttles from nuclear to cytoplasmic sites, forming a complex with the PDZ-LIM protein LMP4 on the actin cytoskeleton. In this study, using a developmental series of chicken hearts, we provide the first evidence for differential Tbx5 protein expression and sub-cellular localization during cardiogenesis. At the tissue level, we show temporally and spatially restricted Tbx5 co-expression with LMP4. In cells co-expressing LMP4 and Tbx5 we demonstrate dynamic Tbx5 re-localization from exclusively nuclear to nuclear and cytoplasmic expression in the atrio-ventricular cushion. Furthermore, in coronary vessel development we show exclusive cytoplasmic localization of Tbx5, indicating a function for Tbx5 in the cytoplasm. In addition, we discover unknown regulation of Tbx5 and LMP4 expression in epicardial tissue, suggesting a specific role for Tbx5 in epicardial formation. These studies provide in vivo significance of the LMP4/Tbx5 protein interaction, suggesting both nuclear and cytoplasmic roles for Tbx5. The shuttling between nuclear and cytoplasmic sites reveals a novel mechanism for Tbx transcription factor regulation in chicken heart development allowing new insights for a better understanding of the molecular basis of hand/heart birth defects associated with TBX5 mutations.

Active Transport, Cell Nucleus↗
PubMed2025

Charting Postnatal Heart Development Using In Vivo Single-Cell Functional Genomics.

The transition at birth, marked by increased circulatory demands and rapid growth, necessitates extensive remodeling of the heart's structure, function, and metabolism. This transformation requires precise spatial and temporal coordination among diverse cardiac cell types; central to this process is cardiomyocyte maturation, yet the regulatory mechanisms driving these changes remain poorly understood. Here, we present a temporal and spatial atlas of postnatal hearts by integrating single-nucleus transcriptomics with image-based spatial transcriptomics, which uncovers the dynamic regulatory networks of cardiomyocyte maturation. To functionally interrogate candidate regulators in vivo , we developed Probe-based Indel-detectable Perturb-seq (PIP-seq), a high-throughput platform that uses probe-based chemistry to directly capture sgRNA expression, perturbation status, and transcriptomic profiles at single-nucleus resolution. Applying PIP-seq to postnatal cardiac development identified 21 novel regulators of cardiomyocyte maturation, highlighting critical nodal points in this process. Our study establishes a high-resolution framework for dissecting postnatal heart development, underscoring the integrative and highly ordered roles of microenvironment and intercellular communication in cardiomyocyte maturation. Importantly, PIP-seq enables systematic, high-throughput exploration of gene function and networks underlying complex biological processes in their native in vivo context.

Journal Article↗
PubMed1996

Insulin-like growth factor-II/mannose-6-phosphate receptor expression during early heart development.

Expression of the insulin-like growth factor-II/mannose-6-phosphate (ICF-II/ M6P) receptor was examined during the major stages of heart morphogenesis in the chicken embryo. By using an affinity-purified antibody, Western blot analysis of total embryonic proteins from stages 5-24 revealed little if any IGF-II/M6P receptor protein until stage 7, approximately 8 hours prior to the appearance of the rudimentary myocardial tubes. Thereafter, receptor accumulation increased until stage 14, after which receptor protein levels remained constant, up to 7 days in ovo. Immunohistochemical localization revealed that, among all embryonic tissues at stages 10-24, the predominant site of receptor expression was the developing myocardium. Receptor expression was also immunohistochemically evaluated in a defined in vitro model of cardiogenesis in which explanted precardiac mesoderm is induced to undergo differentiation by co-explanted endoderm. In this system, as in vivo, IGF-II/M6P receptors were only detected after precardiac mesoderm had differentiated into a synchronously contractile multilayer which expressed cardiac alpha-actin. These findings indicate that the IGF-II/M6P receptor has an important role during early heart development.

Animals↗