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PubMed2006

The matricellular protein CCN1 is essential for cardiac development.

The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1-null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in approximately 20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1(+/-) mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans.

Animals↗
PubMed2000

The expression of SR calcium transport ATPase and the Na(+)/Ca(2+)Exchanger are antithetically regulated during mouse cardiac development and in Hypo/hyperthyroidism.

The mouse has been used extensively for generating transgenic animal models to study cardiovascular disease. Recently, a number of transgenic mouse models have been created to investigate the importance of sarcoplasmic reticulum (SR) Ca(2+)transport proteins in cardiac pathophysiology. However, the expression and regulation of cardiac SR Ca(2+)ATPase and other Ca(2+)transport proteins have not been studied in detail in the mouse. In this study, we used multiplex RNase mapping analysis to determine SERCA2, phospholamban (PLB), and Na(+)/Ca(2+)-exchanger (NCX-1) gene expression throughout mouse heart development and in hypo/hyperthyroid animals. Our results demonstrate that the expression of SERCA2 and PLB mRNA increase eight-fold from fetal to adult stages, indicating that SR function increases with heart development. In contrast, the expression of the Na(+)/Ca(2+)-exchanger gene is two-fold higher in fetal heart compared to adult. Our study also makes the important observation that in hypothyroidic hearts the NCX-1 mRNA and protein levels were upregulated, whereas the SERCA2 mRNA/protein levels were downregulated. In hyperthyroidic hearts, however, an opposite response was identified. These findings are important and point out that the expression of NCX-1 is regulated antithetically to that of SERCA2 during heart development and in response to alterations in thyroid hormone levels.

Animals↗
PubMed2003

T-box genes and cardiac development.

BACKGROUND: T-box genes play roles in vertebrate gastrulation and in later organogenesis. Their existence in all metazoans examined so far indicates that this is an evolutionarily ancient gene family. Drosophila melanogaster has eight T-box genes, whereas Caenorhabditis elegans has 22. Mammals appear to have at least 18 T-box genes, comprising five subfamilies. METHODS: A full range of cytological, developmental, molecular and genetic methodologies have recently been applied to the study of T-box genes. RESULTS: Over the last 5 years, mutations in TBX1 and TBX5 have been implicated in two human disorders with haplo-insufficient cardiovascular phenotypes, DiGeorge/velocardiofacial syndrome and Holt-Oram ("heart-hand") syndrome. Interestingly, the number of T-box gene family members discovered to have cardiac or pharyngeal arch expression domains during vertebrate embryonic development has steadily grown. In addition, various Tbx5 loss-of-function models in organisms as distant as the mouse and zebrafish do indeed phenocopy Holt-Oram syndrome. Finally, the intriguing discovery earlier this year that a T-box gene is expressed in a subset of cardioblasts in D. melanogaster suggests that members of this gene family may have fundamental, conserved roles in cardiovascular pattern formation. CONCLUSIONS: These developments prompted us to review the current understanding of the contribution of T-box genes to cardiovascular morphogenesis.

Abnormalities, Multiple↗
PubMed1999

jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background.

The recessive mutant mouse jumonji (jmj), obtained by a gene trap strategy, shows neural tube defects in approximately half of homozygous embryos with a BALB/cA and 129/Ola mixed background, but no neural tube defects with BALB/cA, C57BL/6J, and DBA/2J backgrounds. Here, we show that neural tube and cardiac defects are observed in all embryos with a C3H/HeJ background. In addition, abnormal groove formation and prominent flexure are observed on the neural plate with full penetrance, suggesting that abnormal groove formation leads to neural tube defects. We found morphogenetic abnormalities in the bulbus cordis (future outflow tract and the right ventricle) of homozygous embryo hearts. Moreover, myocytes in the ventricular trabeculae show hyperplasia with cells filling the ventricles. Together with the observation that the jmj gene is expressed in the neural epithelium of the head neural plate and in myocytes in the bulbus cordis and trabeculae, the results show that the jmj gene plays essential roles in the normal development of the neural plate, morphogenesis of bulbus cordis, and proliferation of trabecular myocytes on a C3H/He background.

Animals↗
PubMed1998

Regulation of carbohydrate and fatty acid utilization by L-carnitine during cardiac development and hypoxia.

This study is designed to investigate whether substrate preference in the myocardium during the neonatal period and hypoxia-induced stress is controlled intracellularly or by extracellular substrate availability. To determine this, the effect of exogenous L-carnitine on the regulation of carbohydrate and fatty acid metabolism was determined during cardiac stress (hypoxia) and during the postnatal period. The effect of L-carnitine on long chain (palmitate) and medium chain (octonoate) fatty acid oxidation was studied in cardiac myocytes isolated from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week old (HY) piglets. Palmitate oxidation was severely decreased in NB cells compared to those from 2 week animals (0.456+/-0.04 vs. 1.207+/-0.52 nmol/mg protein/30 min); surprisingly, cells from even older hypoxic animals appeared shifted toward the new born state (0.695+/-0.038 nmol/mg protein/30 min). Addition of L-carnitine to the incubation medium, which stimulates carnitine palmitoyl-transferase I (CPTI) accelerated palmitate oxidation 3 fold in NB and approximately 2 fold in HY and 2 week cells. In contrast, octanoate oxidation which was greater in new born myocytes than in 2 week cells, was decreased by L-carnitine suggesting a compensatory response. Furthermore, oxidation of carbohydrates (glucose, pyruvate, and lactate) was greatly increased in new born myocytes compared to 2 week and HY cells and was accompanied by a parallel increase in pyruvate dehydrogenase (PDH) activity. The concentration of malonyl-CoA, a potent inhibitor of CPTI was significantly higher in new born heart than at 2 weeks. These metabolic data taken together suggest that intracellular metabolic signals interact to shift from carbohydrate to fatty acid utilization during development of the myocardium. The decreased oxidation of palmitate in NB hearts probably reflects decreased intracellular L-carnitine and increased malonyl-CoA concentrations. Interestingly, these data further suggest that the cells remain compliant so that under stressful conditions, such as hypoxia, they can revert toward the neonatal state of increased glucose utilization.

Animals↗
PubMed1993

Effects of thyroid hormones on cardiac development in oculo.

Embryonic rat myocardium was grafted into the anterior eye chamber (in oculo) of adult host rats in a series of two experiments that studied the effects of thyroid hormones [triiodothyronine (T3) and thyroxine (T4)] on heart tissue developing without hemodynamic load. In each experiment, surgical sympathectomy of one eye chamber was used to define possible interactions between thyroid hormones and sympathetic innervation to the graft. In the first experiment, propylthiouracil (PTU, 20 mg/kg sc) greatly suppressed growth and beating rate of whole heart grafts, while excess T4 (0.1 mg/kg sc) transiently increased beating rate but not growth. In the second experiment, T3 (5 mg/21 days, slow-release pellet) failed to promote growth in ventricular grafts. However, the size of atrial grafts in surgically sympathectomized eye chambers was larger in T3-treated compared with control rats. T3 administration increased beating rate in ventricular grafts. In both experiments, thyroid hormone treatments were effective in increasing heart weight-to-body weight ratios in the host rats. The data suggest that exposure to normal levels of thyroid hormones may be necessary for optimal cardiac growth. The data also support the hypothesis that a hemodynamic load is required for thyroid hormone-induced cardiac growth.

Animals↗
PubMed1989

Immunofluorescent localization of desmin and vimentin in developing cardiac muscle of Syrian hamster.

The distributions of desmin and vimentin were examined in frozen sections of cardiac muscle from embryonic, newborn, and adult Syrian hamster by using immunofluorescent methods. Frozen sections of newborn and adult skeletal muscle were used for comparison. Cardiac myocytes from day 9 in utero embryos already show a clear association of desmin with the sarcomeric myofibrils. In newborn hearts, desmin is localized in the myofibrillar Z-line areas as well as in the peripheral cytoplasm of the cell. Three days after birth, desmin is associated with the intercalated discs. Thus, in adult cardiac muscle, desmin is present in both Z-bands and intercalated discs. Skeletal muscle of newborn and adult hamster also contains desmin associated with the Z-lines of myofibrils. Vimentin is associated with the myofibrils of day 9 in utero cardiac muscle cells. The protein remains associated with the myofibrillar Z-lines in the newborns and adults. No detectable staining for vimentin was observed in newborn or adult hamster skeletal muscle. The existence of vimentin as well as desmin in differentiated cardiac muscle may be a consequence of the somewhat more epithelial-like nature of cardiac cells as compared to skeletal muscle syncitia.

Animals↗
PubMed1997

Telomerase activity during cardiac development.

Telomerase is a ribonucleoprotein involved in maintaining telomere length in stem cells and immortal and actively dividing cells. We report here for the first time that telomerase is developmentally regulated in the normal rat heart. When we compared rat hearts at different developmental stages, we found that telomerase activity decreased to 20% of the fetal level by 5 days after birth, and was undetectable by 20 days after birth. These results indicate that the rate of cardiomyocyte proliferation decreases dramatically soon after birth in the rat. Of several non-cardiac tissues examined, telomerase activity was highest in fetal and adult rat liver, suggesting that there is an active mechanism for maintaining long telomeres in liver tissue at all stages. The disappearance of telomerase activity in the rat heart at the time that cardiomyocytes become terminally differentiated suggests that telomerase downregulation is important in the permanent withdrawal of cardiomyocytes from the cell cycle.

Animals↗
PubMed1994

Localization of transcription factor GATA-4 to regions of the mouse embryo involved in cardiac development.

To clarify the role of transcription factor GATA-4 in mammalian development, we have determined the pattern of expression of GATA-4 in early postimplantation mouse embryos. Using in situ hybridization and immunohistochemistry, we find that GATA-4 RNA and protein are expressed in cells associated with heart development. Intraembryonic expression of GATA-4 RNA is first apparent in coelomic epithelial cells of the primitive streak embryo (approximately 7.0-7.5 days postcoitum). During formation and bending of the heart tube (approximately 8 days postcoitum), GATA-4 RNA and protein are expressed in endocardium, myocardium, and embryonic structures containing precardiac mesoderm such as the septum transversum and intraembryonic coelomic epithelium. By the onset of cardiac septation (approximately 9 days postcoitum), abundant GATA-4 RNA expression is evident in endocardium, endocardial cushion tissue, and myocardium. Expression of GATA-4 by the myocardium continues through gestation and after birth. The temporal and spacial patterns of GATA-4 expression support a role for this factor in the regulation of cardiac differentiation, analogous to the established role of transcription factor GATA-1 in the regulation of hematopoiesis.

Animals↗
PubMed2006

Regulatory mechanisms of cardiac development and repair.

The heart originates from bilateral primordia that eventually fuse in the embryonic midline leading to a linear tube. Soon after, the heart bends to the right and atrial and ventricular chambers are formed. Progressively each embryonic compartment initiates a process of septation that eventually leads to a four chambered heart with a double circuitry and synchronous contraction. During these developmental events, the growth of the heart and in particular of its myocardial component gradually increases. However, as the heart gets into its mature stage, myocardial growth ceases and concomitantly the myocardium looses its proliferative capacity. In the adult human population, the most frequent cardiac pathologies emanate from a decompensated lost of myocardial function. Therapeutical approaches aiming to add or replace new myocytes to the failing heart are thus highly desired. Embryonic stem cells have a high capacity to give rise to multiple cell types, including myocardial cells, opening new therapeutical possibilities. Unexpectedly discrete adult cell populations have also shown a greater cell plasticity than previously thought, earning therefore much attention as therapeutic targets. These observations have launched initial clinical trials with great hope of clinical benefit. However, it is essential in this respect to initially understand, and eventually control myogenic cell fate determination. Developmental biology of the heart provides a very suitable model for this end. Over the last decade there has been a considerable advance in the understanding of the molecular mechanisms that lead to the determination of the cardiomyocyte lineage and the regulatory mechanisms by which morphogenesis of the heart takes place. Growth factor signalling and transcriptional events controlling cardiac myogenesis have been progressively unravelled. In this review we aim to summarise current data concerning the cardiomyogenic cell fate determination pathways occurring during the natural process of cardiogenesis as compared to the myogenic lineages obtained from embryonic and adult stem cells. Identification of key elements provides important resources to which drugs can be targeted and eventually can result in promising tools to control and expand cardiomyocyte determination.

Animals↗
PubMed1999

Advances in understanding the molecular regulation of cardiac development.

Although impressive progress has been made in the diagnosis and treatment of congenital heart disease, there has been an explosion of new information about the basic molecular mechanisms that control normal heart development and subsequent congenital cardiovascular malformations. Since the advent of targeted null mutations in mice (gene "knockouts"), it has become increasingly evident that defects in the heart and vascular system frequently result from gene alterations and that these defects are often responsible for in utero demise. New genes have been discovered that control looping of the heart, distinguish arteries from veins, and direct formation of the semilunar valve and atrioventricular valves. A pivotal role for several genes expressed by the cardiac neural crest document the importance of these cells in aortic arch selection, in addition to their role in aorticopulmonary septation. In addition, myocardial and endothelial progenitor cells have been isolated from bone marrow stromal cells, and human embryonic stem cells have been successfully isolated, paving the way for developmental approaches to tissue engineering and organ regeneration. Finally, the first successful attempt at in utero manipulation of genes that might palliate certain forms of congenital heart disease has been presented. These recent advances are detailed in this article.

Animals↗
PubMed1993

RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development.

We have performed a detailed analysis of the localisations of RNAs for TGF beta 2 and beta 3, and of TGF beta 2 protein in mouse embryos from 6.5 to 9.5 days post coitum, using in situ hybridisation and immunohistochemistry on serial sections, and whole-mount in situ hybridisation to complete embryos. TGF beta 3 RNA was not seen in any of the tissue sections, but very low levels of the RNA were seen by whole-mount in situ hybridisation around the outflow tract of the heart at 8.5 days post coitum. TGF beta 2 RNA is expressed at high levels in all cells with the potential to differentiate into cardiomyocytes. Additionally, the foregut endoderm, juxtaposed to the heart, and the neuroepithelium at the rostral extremity of the foregut, express very high levels of TGF beta 2 RNA, between 8.5 and 9.5 days post coitum. As cardiomyogenesis proceeds, TGF beta 2 RNA levels diminishes within the myocytes, with a concomitant increase in staining for TGF beta 2 protein. TGF beta 2 protein staining of cardiomyocytes persists throughout development and in the adult, in the absence of detectable levels of the corresponding RNA. Superimposed upon this myocardial pattern of expression, there is an upregulation of TGF beta 2 RNA in the myocardium of the outflow tract and atrioventricular canal between 8.5 and 9.5 days post coitum, which returns to low levels by 11.5 days post coitum. The results are discussed in terms of a potential role of TGF beta 2 in controlling cardiomyogenesis and in inductive interactions leading to cardiac cushion tissue formation.

Animals↗
PubMed2006

Tgfbeta signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development.

The transforming growth factorbeta (Tgfbeta) signaling pathway plays crucial roles in many biological processes. To understand the role(s) of Tgfbeta signaling during cardiogenesis in vivo and to overcome the early lethality of Tgfbr2(-/-) embryos, we applied a Cre/loxp system to specifically inactivate Tgfbr2 in either the myocardium or the endothelium of mouse embryos. Our results show that Tgfbr2 in the myocardium is dispensable for cardiogenesis in most embryos. Contrary to the prediction from results of previous in vitro collagen gel assays, inactivation of Tgfbr2 in the endocardium does not prevent atrioventricular cushion mesenchyme formation, arguing against its essential role in epithelium-mesenchyme transformation in vivo. We further demonstrate that Tgfbeta signaling is required for the proper remodeling of the atrioventricular canal and for cardiac looping, and that perturbation in Tgfbeta signaling causes the double-inlet left ventricle (DILV) defect. Thus, our study provides a unique mouse genetic model for DILV, further characterization of which suggests a potential cellular mechanism for the defect.

Animals↗
PubMed2005

Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development.

The coxsackievirus-adenovirus receptor (CAR) is a cell contact protein on various cell types with unknown physiological function. It belongs to a subfamily of the immunoglobulin-superfamily of which some members are junctional adhesion molecules on epithelial and/or endothelial cells. CAR is dominantly expressed in the hearts and brains of mice until the newborne phase after which it becomes mainly restricted to various epithelial cells. To understand more about the physiological function of CAR, we have generated CAR-deficient mice by gene targeting. We found that these mice die between E11.5 and E13.5 of embryonal development. Ultrastructural analysis of cardiomyocytes revealed that the density of myofibrils was reduced and that their orientation and bundling was disorganized. In addition, mitochondria were enlarged and glycogen storage strongly enriched. In line with these defects, we observed pericardial edema formation as a clear sign of insufficient heart function. Developmental abnormalities likely to be secondary effects of gene ablation were the persistent singular cardial atrio-ventricular canal and dilatations of larger blood vessels such as the cardinal veins. The secondary nature of these defects was supported by the fact that CAR was not expressed on vascular cells or on cells of the vascular wall. No obvious signs for alterations of the histological organization of the placenta were observed. We conclude that CAR is required for embryonal heart development, most likely due to its function during the organization of myofibrils in cardiomyocytes.

Animals↗
PubMed2002

Early signals in cardiac development.

The heart is the first organ to form during embryogenesis and its circulatory function is critical from early on for the viability of the mammalian embryo. Developmental abnormalities of the heart have also been widely recognized as the underlying cause of many congenital heart malformations. Hence, the developmental mechanisms that orchestrate the formation and morphogenesis of this organ have received much attention among classical and molecular embryologists. Due to the evolutionary conservation of many of these processes, major insights have been gained from the studies of a number of vertebrate and invertebrate models, including mouse, chick, amphibians, zebrafish, and Drosophila. In all of these systems, the heart precursors are generated within bilateral fields in the lateral mesoderm and then converge toward the midline to form a beating linear heart tube. The specification of heart precursors is a result of multiple tissue and cell-cell interactions that involve temporally and spatially integrated programs of inductive signaling events. In the present review, we focus on the molecular and developmental functions of signaling processes during early cardiogenesis that have been defined in both vertebrate and invertebrate models. We discuss the current knowledge on the mechanisms through which signals induce the expression of cardiogenic transcription factors and the relationships between signaling pathways and transcriptional regulators that cooperate to control cardiac induction and the formation of a linear heart tube.

Animals↗