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At least 289 records · Page 16Linked to original sources
PubMed1991

Distribution of the neural cell adhesion molecule (NCAM) during heart development.

The neural cell adhesion molecule, NCAM, was localized in the embryonic chick heart from Hamburger-Hamilton stage 14 up to hatching and in the adult heart. A monoclonal antibody directed to NCAM was used with the indirect antibody technique to stain frozen sections with immunoperoxidase. The myocardium showed immunoreactivity at stages 15 and 21, with little to no staining of epicardium, endocardium or atrioventricular endocardial cushion tissue. At stage 22, additional immunoreactivity was found in the endocardium of both the atrial septum and the atrial and ventricular surfaces of the atrioventricular cushions. Endocardial-derived mesenchymal cells within the cushions were also immunostained for NCAM. A gradient of NCAM staining was evident in the ventricular wall by stage 16. The staining intensity in the myocardium subjacent to the epicardium was less than found near the ventricular lumen. Biochemical analyses revealed that the embryonic heart expresses polysialylated NCAM. Upon desialylation with the endoneuraminidase Endo-N, the predominant heart NCAM has an apparent molecular weight of 155 to 160 kDa, which is distinct in size from the predominant forms found in embryonic chick nervous system (180, 140 and 120 kDa). NCAM expression is regionally regulated in the heart. The pattern of its expression is consistent with our hypothesis that it is involved in (1) differentiation of the atrial and ventricular walls, (2) fusion of the atrial septum with the endocardial cushions, (3) fusion of the endocardial cushions, and (4) formation and remodeling of ventricular trabeculae.

Animals↗
PubMed1995

Differential expression of alpha- and beta-enolase genes during rat heart development and hypertrophy.

We have analyzed the transition between isoforms of the glycolytic enzyme enolase (2-phospho-D-glycerate hydrolyase; EC 4.2.1.11) in rat heart during normal and pathological growth. A striking fall in embryonic alpha-enolase gene expression occurs during cardiac development, mostly controlled at pretranslational steps. In fetal and neonatal hearts, muscle-specific beta-enolase gene expression is a minor contributor to total enolase. Control mechanisms of beta-enolase gene expression must include posttranscriptional steps. Aortic stenosis induces a rapid and drastic decrease in beta-enolase transcript level in cardiomyocytes, followed by the fall in beta-subunit level. In contrast, alpha-enolase transcript level is not significantly altered, although the corresponding subunit level increases in nonmuscle cells. We conclude that, like fetal heart, hypertrophic heart is characterized by a high ratio of alpha- to beta-enolase subunit concentrations. This study indicates that the decrease in beta-enolase gene expression may be linked to beneficial energetic changes in contractile properties occurring during cardiac hypertrophy.

Aging↗
PubMed1996

Type VI collagen in the cardiac valves and connective tissue septa during heart development.

A variety of extracellular matrix (ECM) proteins have been shown to be present in the embryonic heart during the morphogenesis of the valves and membranous septa. It is not known if any specific ECM protein is required for the normal morphogenesis of these tissues, but this is of great interest since there is a high incidence of congenital malformations which affect valvular and septal tissues. Interestingly, the alpha 1 and alpha 2 genes of type VI collagen are located within the region of human chromosome 21 thought to be involved in the congenital heart defect phenotype associated with trisomy 21 (Down's syndrome). In this study we examined the distribution and investigated the function of type VI collagen in the cardiac valves and septa of chicken and mouse embryos during various stages of development. Immunohistochemical and in situ hybridization studies revealed a pattern of cardiac expression of type VI collagen which is present from the earliest stages of valve and septum development through the neonatal period. Results from an in vitro bioassay suggest that type VI collagen may play a role in the formation and migration of specific cells in the forming valves and septa. These data support molecular genetic studies which have indicated that type VI collagen is involved in the heart defect phenotype seen in trisomy 21.

Animals↗
PubMed1996

[A case of a univentricular heart developed subaortic stenosis after fontan operation].

The patient was a seven-old-boy with univentricular heart of left ventricular morphology with transposition of the great arteries and coarctation of the Aorta. Pulmonary artery banding and coarctactomy (subclavian flap method) were performed as prior surgery during infancy and significant subaortic stenosis (SAS) was not identified before or immediately after Fontan operation. SAS was suspected in an ejection murmur that developed without symptoms two years and five months after Fontan operation. It became clear that the SAS was caused by both restrictive ventricular septal defect and narrowing of outlet chamber (right ventricle). Surgery was performed with myectomy in the outlet chamber, enlargement of ventricular septal defect and a patch enlargement of the right ventricle outflow tract for relief of the SAS. Postoperative pressure gradient across the subaortic component was decreased, however, valve regurgitation remained grade I to II. The mechanisms of SAS after Fontan operation are related to hypertrophy of the subaortic component that incorporates the infundibulum and trabeculae. Careful morphological investigation is essential in patients with risk factors for SAS Mild deterioration of the ventricular compliance due to progressive SAS may result in reduction of the cardiac function and patient's quality of life. Adequate surgical treatment to relieve the SAS is considered essential before and after Fontan operation.

Aortic Coarctation↗
PubMed2006

ErbB and HB-EGF signaling in heart development and function.

The epidermal growth factor (EGF)-ErbB signaling network is composed of multiple ligands of the EGF family and four tyrosine kinase receptors of the ErbB family. In higher vertebrates, these four receptors bind a multitude of ligands. Ligand binding induces the formation of various homo- and heterodimers of ErbB, potentially providing for a high degree of signal diversity. ErbB receptors and their ligands are expressed in a variety of tissues throughout development. Recent advances in gene targeting strategies in mice have revealed that the EGF-ErbB signaling network has fundamental roles in development, proliferation, differentiation, and homeostasis in mammals. The heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor (EGFR/ErbB1) and ErbB4. Recent studies using several mutant mice lacking HB-EGF expression have revealed that HB-EGF has a critical role in normal heart function and in normal cardiac valve formation in conjunction with ErbB receptors. HB-EGF signaling through ErbB2 is essential for the maintenance of homeostasis in the adult heart, whereas HB-EGF signaling through EGFR is required during cardiac valve development. In this review, we introduce and discuss the role of ErbB receptors in heart function and development, focusing on the physiological function of HB-EGF in these processes.

Animals↗
PubMed1999

Cell lineage tracing in heart development.

Photolysis-based lineage determination is especially useful in addressing late-stage lineage definitions. Although we have focused on the heart lineage, this technique is readily applicable to any region of the embryo. Furthermore, the concomitant analysis of gene expression and lineage restriction within the same embryo will help define the signaling cascades that direct normal cell fate and the regulative changes that mark vertebrate organ development.

Animals↗
PubMed2005

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation.

Signaling pathways underlying transition of cardiomyocyte growth from hyperplasia in fetal/newborn to hypertrophy in postnatal/adult hearts are not well understood. We have shown that beta-adrenergic receptor (beta-AR)-mediated regulation of neonatal cardiomyocyte proliferation involves p70 ribosomal protein S6 kinase (p70S6K). Here we examined the ontogeny of phosphoinositide 3-kinase (PI3K)/p70S6K signaling pathway in rat hearts and investigated the influence of beta-AR on this pathway during development. Cardiac PI3K and p70S6K1 activities were high in the embryonic day 20 fetus, decreased gradually postnatally, and were low in the adult. In contrast, p70S6K2 was barely detectable. Phosphorylation of p70S6K1, Akt, and phosphoinositide-dependent protein kinase 1 were markedly increased in late gestation and early postnatal life but not in adult hearts. Phosphatase and tensin homolog on chromosome 10 (PTEN), a negative regulator of PI3K, was highly expressed in adult hearts but only at low levels and mostly in the phosphorylated (inactivated) form in the fetus. Beta-AR stimulation resulted in increased cardiac p70S6K1 activity only in animals > or = 2 wk old, whereas Akt level was increased in all developmental stages tested. These increases were accompanied by increased Bcl-2 associated death promoter (Ser136) phosphorylation without changes in PTEN level. Thus there is globally high input of cardiac PI3K signaling during the fetal-neonatal transition period. Inactivation of PTEN may in part contribute to the high activity of PI3K signaling, which coincides with the period of high cardiomyocyte proliferation. Beta-AR stimulation activates cardiac p70S6K1 and Akt in postnatal animals and may activate cardiac survival signals. These data provide further evidence for the importance of beta-AR and PI3K signaling in the regulation of cardiac growth during development.

Adrenergic beta-Agonists↗
PubMed2004

Maternal methamphetamine administration during pregnancy influences on fetal rat heart development. [corrected].

Methamphetamine (MAP) is one of the most abused drugs in Japan. The rate of MAP abuse by young women has recently reached more than 50 percent in adolescents. A major health concern is that these women will continue to use MAP during pregnancy. The purpose of this study was to investigate whether MAP administered to the mother during pregnancy would change the expression of alpha- and beta- myosin heavy chain (MHC) mRNA in rat neonatal hearts, as detected by quantitative RT-PCR. In addition, morphological changes in the rat neonatal ventricles were examined. Pregnant rats were injected intraperitoneally with MAP (1 mg/kg/day) starting at day 0 of gestation and ending at day 21. There was a significant increase in alpha-MHC mRNA expression in the neonatal ventricular muscle in the experimental group compared with the control at postnatal day (P) 0 and 5. alpha-MHC mRNA expression in both groups was similar after P9. beta-MHC mRNA expression was similar in both groups at P0. Postnatal beta-MHC mRNA expression decreased rapidly, but significant alteration was not detected. Neonatal rats at P0 exhibited some cardiac changes, including hypertrophy, degeneration, and disarrangement of myofibers, but these lesions disappeared by P14. We conclude that chronic maternal administration of MAP changes the alpha- and beta-MHC mRNA expression pattern in fetal and neonatal hearts, correlating with abnormal development, plasma level of hormones, and myocardial damage. At the same time, it is indicated that neonatal cardiomyocytes have reversibility.

Adolescent↗
PubMed2003

Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart.

Tbx20 is a member of the T-box transcription factor family expressed in the forming hearts of vertebrate and invertebrate embryos. We report here analysis of Tbx20 expression during murine cardiac development and assessment of DNA-binding and transcriptional properties of Tbx20 isoforms. Tbx20 was expressed in myocardium and endocardium, including high levels in endocardial cushions. cDNAs generated by alternative splicing encode at least four Tbx20 isoforms, and Tbx20a uniquely carried strong transactivation and transrepression domains in its C terminus. Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site, although with less avidity compared with the related factor, Tbx5. Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression. Among cardiac GATA factors, there was preferential synergy with GATA5, implicated in endocardial differentiation. In Xenopus embryos, enforced expression of Tbx20a, but not Tbx20b, led to induction of mesodermal and endodermal lineage markers as well as cell migration, indicating that the long Tbx20a isoform uniquely bears functional domains that can alter gene expression and developmental behaviour in an in vivo context. We propose that Tbx20 plays an integrated role in the ancient myogenic program of the heart, and has been additionally coopted during evolution of vertebrates for endocardial cushion development.

Alternative Splicing↗
PubMed2004

Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway.

Malformations of the septum, outflow tract and aortic arch are the most common congenital cardiovascular defects and occur in mice lacking Cited2, a transcriptional coactivator of TFAP2. Here we show that Cited2(-/-) mice also develop laterality defects, including right isomerism, abnormal cardiac looping and hyposplenia, which are suppressed on a mixed genetic background. Cited2(-/-) mice lack expression of the Nodal target genes Pitx2c, Nodal and Ebaf in the left lateral plate mesoderm, where they are required for establishing laterality and cardiovascular development. CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays. We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2(-/-) mice, and that such malformations may be the sole manifestation of a laterality defect.

Animals↗
PubMed1998

The role of the brachyury gene in heart development and left-right specification in the mouse.

The midline has a theoretical role in the development of left-right asymmetry, and this is supported by both genetic analyses and experimental manipulation of midline structures in vertebrates. The mouse brachyury (T) gene encodes a transcription factor which is expressed in the developing notochord and is required for its development. T/T mice lack a mature notochord and have a dorsalised neural tube. We have examined the hearts of T/T mice and have found consistent morphological abnormalities, resulting in ventrally displaced ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta related genes, lefty-1, lefty-2 and nodal, are expressed asymmetrically in mouse embryos, and are implicated in the development of situs. We find that nodal, which is normally expressed around the node and in left lateral plate mesoderm in early somite embryos, is completely absent at this stage in T/T embryos. In contrast, lefty-1 and lefty-2, which are normally expressed in the left half of prospective floorplate and left lateral plate mesoderm, respectively, are both expressed in T/T embryos only in a broad patch of ventral cells in, and just rostral to, the node region. These results implicate the node as a source of instructive signals driving expression of nodal and lefty-2 in the left lateral plate mesoderm, and being required for normal looping and situs of the heart.

Animals↗
PubMed1990

Effects of isoproterenol on the developing heart in rats.

Many clinical clues suggest a link between abnormal catecholamine function during a phase of rapid cardiac development and hypertrophic cardiomyopathy. However, experimental investigation focusing on abnormal catecholamine function during the fetal period as the pathogenesis of hypertrophic cardiomyopathy has not yet been carried out. In this study, isoproterenol (ISO) was administered to pregnant female rats and the effects of the drug on the hearts of their offspring were studied morphologically. Fifty micrograms/kg/day of ISO was administered subcutaneously to 15 pregnant female rats 5 days a week for 3 weeks and the offspring were killed at 2 days, 4 weeks or 7 weeks after birth. Isotonic saline was administered to 15 pregnant female rats as control. The hearts of the offspring were removed and weighed immediately. The ventricles were cut in two, parallel to the atrio-ventricular groove. Left and right ventricular free wall thickness and interventricular septal thickness were measured. Under light-microscope, myocardial fiber diameter was measured and myocardial fiber disarray was assessed. Fine structural alterations of the cardiac muscle cells were observed by an electron microscope. The hearts of newborn offspring from pregnant rats treated with ISO showed disproportionate septal hypertrophy and frequent inter- and intra-cellular disarray in the interventricular septum. However, these changes were not prominent at 7 weeks after birth. These results suggest that abnormal catecholamine function during the fetal period may result in disproportionate septal hypertrophy.

Animals↗
PubMed1987

Isomyosin expression patterns in tubular stages of chicken heart development: a 3-D immunohistochemical analysis.

The 3-D distribution of atrial and ventricular isomyosins is analysed in tubular chicken hearts (stage 12+ to 17 (H/H)) using antibodies specific for adult chicken atrial and ventricular myosin heavy chains, respectively. At stage 12+ (H/H) all myocytes express the atrial isomyosin; furthermore, all myocytes except those originally situated in the dorsolateral wall of the sinu-atrium coexpress the ventricular isomyosin as well. Moreover, it appears that recently incorporated myocardial cells at both ends of the heart tube start with a coexpression of both isomyosins. From stage 14 (H/H) onwards a regional loss of expression of one of either isomyosins is observed in the atrial and ventricular compartment. In this way the single isomyosin expression types that are characteristic for the adult working myocardium of the atria and ventricles arise. So, the isomyosin expression patterns are, unexpectedly, hardly useful to discriminate the different heart parts of the tubular heart. The ventricle, defined by its adult type of isomyosin expression, is even not detectable before stage 14 (H/H). Interestingly, interconnected coexpression areas, which may be precursor conductive tissues, are still present at stage 17 (H/H) in the outflow tract, the ventricular trabeculae, the atrio-ventricular transitional zone and in the sinu-atrium. The pattern of isomyosin coexpression was found to correlate with a peristaltoid contraction and a slow conduction velocity, whereas single expression areas correlate with a synchronous contraction and a relatively fast conduction velocity. The possible implications of the changing isomyosin pattern for the differentiation of the tubular myocardium, in particular in relation to the development of the conductive tissues, will be discussed.

Animals↗