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At least 127 records · Page 7Linked to original sources
PubMed1992

Expression of alpha-tropomyosin during cardiac development in the chick embryo.

A new monoclonal antibody (mAb) that recognizes alpha-tropomyosin in cardiac muscle cells was used in a qualitative (polyacrylamide gel electrophoresis and indirect immunofluorescence) and quantitative (fluorescence-activated cell sorting) study of the expression of this protein during heart development. alpha-Tropomyosin expression was weak in early stages of chick embryo development (Hamburger and Hamilton stage 18), and increased steadily until Hamburger Hamilton stage 40. In early stages, the protein was found mainly in cytoplasm, whereas by the final stages, it was more abundant in the cytoskeletal compartment. The mAb cross-reacted with alpha-tropomyosin in smooth and striated muscle cells from chickens, mice, and humans, but did not cross-react with nonmuscle tropomyosin.

Animals↗
PubMed2001

Fibulin-2 expression marks transformed mesenchymal cells in developing cardiac valves, aortic arch vessels, and coronary vessels.

Previous studies showed that extracellular matrix protein, fibulin-2, is expressed during epithelial-mesenchymal transformation in the endocardial cushion matrix during embryonic heart development. Our current study revealed that, in addition to the cardiac valvuloseptal formation, fibulin-2 is synthesized by the smooth muscle precursor cells of developing aortic arch vessels and the coronary endothelial cells that are originated from neural crest cells and epicardial cells, respectively. In the cardiac valves and the aortic arch vessels, fibulin-2 expression shows robust up-regulation when the transformed mesenchymal cells migrate into the existing extracellular matrix. In the epicardium, epicardial cells produce fibulin-2 upon their migration over the myocardial surface and its expression persists throughout coronary vasculogenesis and angiogenesis. Fibulin-2 is produced by the endothelial cells of coronary arteries and veins but not by the capillary endothelial cells in the myocardium. Thus, fibulin-2 not only uniquely marks the transformed mesenchymal cells during mouse embryonic cardiovascular development, but also indicates vascular endothelial cells of coronary arteries and veins in postnatal life.

Animals↗
PubMed2003

The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases.

Pitx2 is a bicoid-related homeodomain transcription factor that plays a critical role in directing cardiac asymmetric morphogenesis. Ectopic Pitx2c expression in the developing myocardium correlates with double outlet right ventricle (DORV) in laterality mutants. Pitx2 loss of function experiments cause severe cardiovascular defects, such as atrial isomerism (AI), double inlet left ventricle, transposition of the great arteries (TGA), persistent truncus arteriosus (PTA), and abnormal aortic arch (AAA) remodeling. Current studies suggest that Pitx2-mediated signaling during cardiogenesis is conducted within three different cell types: the myocardium, the cardiac neural crest (CNC) cells, and the pharyngeal arch mesenchyme. Impaired Pitx2 function in discrete myocardial regions seems to lead to DORV, AI, and possibly TGA. On the other hand, impaired Pitx2 expression in the CNC leads preferentially to PTA. AAA remodeling is likely to occur owing to impaired cross-talk of the CNC cells with the pharyngeal arch mesenchyme. Thus, Pitx2 appears to be directing left-right identity to the cardiac venous components (e.g., the atria), whereas it appears to be modeling the morphologic arrangement of distinct myocardial components in the arterial pole. These data suggest that altered left-right signaling underlies the etiology of several common congenital cardiac malformations.

Animals↗
PubMed2002

The role of neural crest during cardiac development in a mouse model of DiGeorge syndrome.

The velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a genetic disorder characterized by phenotypic abnormalities of the derivatives of the pharyngeal arches, including cardiac outflow tract defects. Neural crest cells play a major role in the development of the pharyngeal arches, and defects in these cells are likely responsible for the syndrome. Most patients are hemizygous for a 1.5- to 3.0-Mb region of 22q11, that is suspected to be critical for normal pharyngeal arch development. Mice hemizygous for a 1.5-Mb homologous region of chromosome 16 (Lgdel/+) exhibit conotruncal cardiac defects similar to those seen in affected VCFS/DGS patients. To investigate the role of Lgdel genes in neural crest development, we fate mapped neural crest cells in Lgdel/+ mice and we performed hemizygous neural crest-specific inactivation of Lgdel. Hemizygosity of the Lgdel region does not eliminate cardiac neural crest migration to the forming aortic arches. However, neural crest cells do not differentiate appropriately into smooth muscle in both fourth and sixth aortic arches and the affected aortic arch segments develop abnormally. Tissue-specific hemizygous inactivation of Lgdel genes in neural crest results in normal cardiovascular development. Based on our studies, we propose that Lgdel genes are required for the expression of soluble signals that regulate neural crest cell differentiation.

Animals↗
PubMed1993

Troponin I gene expression during human cardiac development and in end-stage heart failure.

Recent reports have demonstrated the presence of two isoforms of troponin I in the human fetal heart, namely, cardiac troponin I and slow skeletal muscle troponin I. Structural and physiological considerations indicate that these isoforms would confer differing contractile properties on the myocardium, particularly on the phosphorylation-mediated regulation of contractility by adrenergic agonists. We have investigated the developmental expression of these isoforms in the human heart from 9 weeks of gestation to 9 months of postnatal life, using Western blots revealed with troponin I antibodies to detect troponin protein isoforms and Northern blots to detect the corresponding mRNAs. The results show the following: 1) Slow skeletal muscle troponin I is the predominant isoform throughout fetal life. 2) After birth, the slow skeletal isoform is lost, with cardiac troponin I being the only isoform detectable by 9 months of postnatal development. 3) The protein isoforms and their corresponding mRNAs follow the same pattern of accumulation, suggesting that the transition in troponin expression is regulated at the level of gene transcription. The developmental transition in troponin I isoform content has implications for contractility of the fetal and postnatal myocardium. We further analyzed right and left ventricular muscle samples from 17 hearts in end-stage heart failure resulting from pulmonary hypertension, ischemic heart disease, or dilated cardiomyopathy. Cardiac troponin I mRNA remained abundant in each case, and slow skeletal muscle troponin I mRNA was not detectable in any of sample. We conclude that alterations in troponin I isoform content do not therefore contribute to the altered contractile characteristics of the adult failing ventricle.

Adolescent↗
PubMed2003

NFATc3 and NFATc4 are required for cardiac development and mitochondrial function.

Activation of the nuclear factor of activated T-cell (NFAT) family of transcription factors is associated with changes in gene expression and myocyte function in adult cardiac and skeletal muscle. However, the role of NFATs in normal embryonic heart development is not well characterized. In this report, the function of NFATc3 and NFATc4 in embryonic heart development was examined in mice with targeted disruption of both nfatc3 and nfatc4 genes. The nfatc3-/-nfatc4-/- mice demonstrate embryonic lethality after embryonic day 10.5 and have thin ventricles, pericardial effusion, and a reduction in ventricular myocyte proliferation. Cardiac mitochondria are swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis are not evident. Furthermore, enzymatic activity of complex II and IV of the respiratory chain and mitochondrial oxidative activity are reduced in nfatc3-/-nfatc4-/- cardiomyocytes. Cardiac-specific expression of constitutively active NFATc4 in nfatc3-/-nfatc4-/- embryos prolongs embryonic viability to embryonic day 12 and preserves ventricular myocyte proliferation, compact zone density, and trabecular formation. The rescued embryos also maintain cardiac mitochondrial ultrastructure and complex II enzyme activity. Together, these data support the hypothesis that loss of NFAT activity in the heart results in a deficiency in mitochondrial energy metabolism required for cardiac morphogenesis and function.

Animals↗
PubMed1985

Biochemical and functional alterations in renal and cardiac development resulting from neonatal methylmercury treatment.

Administration of methylmercury (1 or 2.5 mg/kg daily) to neonatal rats caused alterations in both cardiac and renal growth patterns. Heart weights were elevated in the preweaning period in association with hyperplasia (supranormal DNA content); after weaning, the cardiac overgrowth regressed and there was an eventual hypoplasia as evidenced by low DNA content in young adulthood. Renal overgrowth was more pronounced and persistent, but reflected a pure hypertrophy, with no changes in DNA. Renal function was affected by neonatal methylmercury exposure, as assessed through basal clearance techniques. In the immediate period after beginning treatment, there was an impairment of renal function (elevated serum urea, creatinine and osmolality; increased fractional excretions of water, sodium and osmotic particles), with a return to normal by 10 days postnatally. Thereafter, there was a secondary phase of tubular impairment which peaked at the time of maximum hypertrophy. Thus, biochemical and functional indices of organ development can be adversely affected at doses of methylmercury which are usually associated primarily with nervous system-specific damage; effects of methylmercury on neuronal and/or hormonal factors may contribute to the perturbations.

Animals↗
PubMed1997

ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice.

Heregulins bind directly to ErbB3 and ErbB4 receptors, leading to multiple dimerization possibilities including heterodimerization with the ErbB2 receptor. We have generated ErbB3-, ErbB2- and heregulin-deficient mice to assess their roles in development and differentiation. Heregulin(-/-) and ErbB2(-/-) embryos died on E10.5 due to a lack of cardiac ventricular myocyte differentiation; ErbB3(-/-) embryos survived until E13.5 exhibiting cardiac cushion abnormalities leading to blood reflux through defective valves. In ErbB3(-/-) embryos, the midbrain/hindbrain region was strikingly affected, with little differentiation of the cerebellar plate. Cranial ganglia defects, while present in all three nulls, were less severe in ErbB3(-/-) embryos. The cranial ganglia defects, along with a dramatic reduction in Schwann cells, enteric ganglia and adrenal chromaffin cells, suggests a generalized effect on the neural crest. Numerous organs, including the stomach and pancreas also exhibited anomalous development.

Adrenal Glands↗
PubMed2006

Collagen XVIII/endostatin is associated with the epithelial-mesenchymal transformation in the atrioventricular valves during cardiac development.

Type XVIII collagen is a multidomain protein that contains cleavable C-terminal NC1 and endostatin fragments, which have been shown to either induce or inhibit cell migration. Endostatin is being intensely studied because of its anti-angiogenic activity. Three variants of type XVIII collagen have been reported to be distributed in epithelial and endothelial basement membranes in a tissue-specific manner. The single gene encoding collagen XVIII is on chromosome 21 within the region associated with the congenital heart disease phenotype observed in Down's syndrome. In this study, we investigated the expression pattern of collagen XVIII in embryonic mouse hearts during formation of the atrioventricular (AV) valves. We found that collagen XVIII is localized not only in various basement membranes but is also highly expressed throughout the connective tissue core of the endocardial cushions and forming AV valve leaflets. It was closely associated with the epithelial-mesenchymal transformation of endothelial cells into mesenchymal cushion tissue cells and was localized around these cells as they migrated into the cardiac jelly to form the initial connective tissue elements of the valve leaflets. However, after embryonic day 17.5 collagen XVIII expression decreased rapidly in the connective tissue and thereafter remained detectable only in the basement membranes of the endothelial layer covering the leaflets. The staining pattern observed within the AV endocardial cushions suggests that collagen XVIII may have a role in cardiac valve morphogenesis. These results may help us to better understand normal heart development and the aberrant mechanisms that cause cardiac malformations in Down's syndrome.

Animals↗
PubMed1990

Optical studies of early developing cardiac and neural activities using voltage-sensitive dyes.

Using optical methods for monitoring cellular electrical activity based on voltage-sensitive dyes, we have overcome several obstacles to the study of electrical function in the embryonic heart and central nervous system during early development. We have been able to monitor, for the first time, spontaneous electrical activity in the pre-fused cardiac primordia in early chick embryos at the 6- and early 7-somite stages of development and to follow the early development of electrical activity in the pre-contractile heart at the 7- to 9-somite stages. In addition, we have monitored neural responses in the early embryonic chick brain stem by optical means, and determined the spatial pattern of the response.

Action Potentials↗
PubMed2004

Basics of cardiac development for the understanding of congenital heart malformations.

Cardiovascular development has become a crucial element of transgene technology in that many transgenic and knockout mice unexpectedly present with a cardiac phenotype, which often turns out to be embryolethal. This demonstrates that formation of the heart and the connecting vessels is essential for the functioning vertebrate organism. The embryonic mesoderm is the source of both the cardiogenic plate, giving rise to the future myocardium as well as the endocardium that will line the system on the inner side. Genetic cascades are unravelled that direct dextral looping and subsequent secondary looping and wedging of the outflow tract of the primitive heart tube. This tube consists of a number of transitional zones and intervening primitive cardiac chambers. After septation and valve formation, the mature two atria and two ventricles still contain elements of the primitive chambers as well as transitional zones. An essential additional element is the contribution of extracardiac cell populations like neural crest cells and epicardium-derived cells. Whereas the neural crest cell is of specific importance for outflow tract septation and formation of the pharyngeal arch arteries, the epicardium-derived cells are essential for proper maturation of the myocardium and coronary vascular formation. Inductive signals, sometimes linked to apoptosis, of the extracardiac cells are thought to be instructive for differentiation of the conduction system. In summary, cardiovascular development is a complex interplay of many cell-cell and cell-matrix interactions. Study of both (transgenic) animal models and human pathology is unravelling the mechanisms underlying congenital cardiac anomalies.

Animals↗
PubMed1995

Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor.

Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.

Animals↗
PubMed1989

Neural cell adhesion molecule (N-CAM) expression during cardiac development in the rat.

Neural cell adhesion molecule (N-CAM) expression was examined in the rat heart using immunohistochemical and immunochemical techniques. N-CAM immunoreactivity was displayed by myocardial cells from embryonic day E12 and by cardiac nerves when first identified at day E18. Myocardial immunostaining increased up until about postnatal day 1 and then declined rapidly thereafter whereas neural immunoreactivity persisted in the adult. N-CAM cardiac isoforms also exhibited developmental changes from the main embryonic moieties (105 and 145 kDa) to the principal postnatal (125 and 155 kDa) and adult isoforms (125 kDa). Cardiac N-CAM expression is therefore subject to temporal regulation and may modulate cellular interactions in the developing heart.

Animals↗
PubMed2000

Expression of atrial natriuretic factor (ANF) during Xenopus cardiac development.

We have isolated the Xenopus orthologue of the atrial natriuretic factor (ANF) gene. Characterization of embryonic expression indicates that the ANF gene is initially expressed throughout the developing myocardium at the late heart tube stage (about stage 32). This is in contrast to all previously characterized Xenopus cardiac differentiation markers that are first expressed in the cardiogenic plate at approximately stage 27. ANF expression becomes restricted exclusively to the atrium at about stage 47, long after the commencement of beating and the original formation of the atrial and ventricular compartments, but shortly after septation of the single atrium into two distinct atria.

Amino Acid Sequence↗
PubMed2000

Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development.

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest-derived tissues, including branchial arch-derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1-null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1(-/-); ECE-2(-/-) double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1(-/-); ECE-2(-/-) embryos at E12.5 do not differ appreciably from those of ECE-1(-/-) embryos. The significant residual ET-1/ET-2 in the ECE-1(-/-); ECE-2(-/-) embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

Animals↗
PubMed2002

Control of cardiac development by an evolutionarily conserved transcriptional network.

Formation of the heart is dependent on an intricate cascade of developmental decisions. Analysis of the molecules and mechanisms involved in the specification of cardiac cell fates, differentiation and diversification of cardiac muscle cells, and morphogenesis and patterning of different cardiac cell types has revealed an evolutionarily conserved network of signaling pathways and transcription factors that underlies these processes. The regulatory network that controls the formation of the primitive heart in fruit flies has been elaborated upon to form the complex multichambered heart of mammals. We compare and contrast the mechanisms involved in heart formation in fruit flies and mammals in the context of a network of transcriptional interactions and point to unresolved questions for the future.

Animals↗
PubMed1992

Distribution of collagens and fibronectin in the subepicardium during avian cardiac development.

The development of the layer of connective tissue between ventricular epicardium and myocardium was studied during chick morphogenesis using electron microscopy, light microscopy and immunohistochemical techniques. This layer, called the subepicardium, increases rapidly in volume from embryonic day 6 to 11 (E6-E11) during mesenchymal cell invasion. Fibrous, matrix components are initially apparent at E11 to E16, and as fibrous connective tissue structures accumulate, subepicardial volume decreases. Antibody labeling shows that fibronectin is an early, prominent constituent of the subepicardium, and by E8, the subepicardium is the cardiac site most enriched in fibronectin. Collagen type III is present in circumferentially-oriented fibers at E8. During subsequent cardiac growth, collagen type III fibers become broadly distributed in the subepicardium, with some fibers appearing to attach myocardium to epicardium. Collagen type I fibers are not apparent until E10. At E12 collagen type I fibers are distributed circumferentially around the heart in bundles crimped into waves of low amplitude. Other collagen type I fibers are oriented radially in the subepicardium. During late cardiac morphogenesis and in fully-differentiated hearts, fibronectin and collagen types I and III are more concentrated in the subepicardium than within the myocardium. These observations suggest that the composition and organization of the subepicardial connective tissue may make important contributions to cardiac mechanics from the latter half of embryonic development through adulthood.

Animals↗