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Antoon F M Moorman

Publications and source records attributed to Antoon F M Moorman.

At least 19 recordsLinked to original sources
PubMed2005

Malformations of the axial skeleton in Museum Vrolik I: homeotic transformations and numerical anomalies.

The Museum Vrolik collection of anatomical specimens in Amsterdam, The Netherlands, comprises over 5,000 specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, we rediagnosed a subset of the collection comprising dried human trunk skeletons and cranial base preparations presenting with homeotic transformations (vertebral phenotypic shifts) and numerical vertebral anomalies. We identified 11 trunk skeletons with either anterior or posterior homeotic transformations (AHT or PHT), 5 trunk skeletons with either less or more than the normal number of vertebrae, and well over a hundred cranial base preparations with either AHT (atlas-assimilation) or PHT (occipital vertebra). We found that, although homeotic transformations and numerical anomalies are distinct conditions, both can be described in terms of mismatch between homeotic patterning and morphological segmentation of the paraxial mesoderm. Therefore these two processes are perhaps not as tightly linked as they may seem on the basis of recent molecular studies. In homeotic transformations there is a constant mismatch between homeotic patterning and morphological segmentation throughout the affected region of the vertebral column. In numerical anomalies there is a variable mismatch between homeotic patterning and morphological segmentation, either because of stretching or squeezing of the homeotic pattern or because of oligo- or polysegmentation of the presomitic mesoderm (PSM). Homeotic transformations of the axial skeleton have an incidence of about 1%-5%, apart from their occurrence in malformation syndromes. Of the various etiological possibilities, explaining their frequent but mostly sporadic occurrence, maternal hyperthermia seems an attractive candidate.

Animals↗
PubMed2005

Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system.

The semaphorins are a large family of proteins involved in the patterning of both the vascular and the nervous systems. In order to analyze the function of the membrane-bound semaphorin 5A (Sema5A), we generated mice homozygous for a null mutation in the Sema5a gene. Homozygous null mutants die between embryonic development days 11.5 (E11.5) and E12.5, indicating an essential role of Sema5A during embryonic development. Mutant embryos did not show any morphological defects that could account for the lethality of the mutation. A detailed analysis of the vascular system uncovered a role of Sema5A in the remodeling of the cranial blood vessels. In Sema5A null mutants, the complexity of the hierarchically organized branches of the cranial cardinal veins was decreased. Our results represent the first genetic analysis of the function of a class 5 semaphorin during embryonic development and identify a role of Sema5A in the regional patterning of the vasculature.

Animals↗
PubMed2004

Molecular and electrical characterization of the canine cardiac ventricular septum.

Electrophysiological heterogeneity in the ventricular septum (VS) has been poorly addressed. In this study we investigated the electrophysiological and molecular composition of the VS in control sinus rhythm (SR) and chronic, complete atrio-ventricular block (CAVB) dogs. In the latter model, we anticipated that the increased inter-ventricular differences in action potential duration (APD; LV >RV) would accentuate the intrinsic heterogeneous composition of the VS. Steady-state mRNA levels of 10 important cardiac ion channels subunits as well as action potential (AP) characteristics (APD95, phase 1 amplitude (P1A), resting membrane potential) were measured in both sides of the VS excluding a small mid-myocardial strip (right: RVS, left: LVS). In SR, differences in steady-state mRNA between the two septal layers were observed for KChIP2 (approximately fivefold, P <0.01) and KCNQ1 (approximately twofold, P <0.05) with significantly higher levels of steady-state mRNA in the RVS compared to LVS. Correspondingly, shorter APDs and lower P1As (more spike and dome) were found in RVS, although the AP differences were subtle. This transseptal expression of KChIP2 and KCNQ1 corresponded with the observed differential expression levels in the right ventricle (RV) and left ventricular (LV) free wall, respectively. Electrical remodeling due to CAVB was also observed in the VS as was shown by approximately twofold lower levels in KCND3, KCNH2 and KCNQ1 mRNA (P <0.05) in the LVS compared to SR, thereby creating new or eliminating existing transseptal gradients. In parallel to changes in steady-state mRNA, CAVB resulted in a loss of the spike and dome morphology and longer APD95 (P <0.05) in the LVS. It is concluded that similar to other regions in the cardiac ventricles, the canine VS is molecularly and electrically heterogeneous. In the CAVB dog, this septal heterogeneity becomes accentuated as a result of electrical remodeling.

Action Potentials↗
PubMed2004

Reconstruction of the patterns of gene expression in the developing mouse heart reveals an architectural arrangement that facilitates the understanding of atrial malformations and arrhythmias.

Firm knowledge about the formation of the atrial components and of the variations seen in congenital cardiac malformations and abnormal atrial rhythms is fundamental to our understanding of the normal structure of the definitive atrial chambers. The atrial region is relatively inaccessible and has continued to be the source of disagreement. Seeking to resolve these controversies, we made three-dimensional reconstructions of the myocardial components of the developing atrium, identifying domains on the basis of differential expression of myocardial markers, connexin40, and natriuretic precursor peptide A. These reconstructions, made from serial sections of mouse embryos, show that from the outset of atrial development, the systemic and pulmonary veins are directly connected to the atrium. Relative to the systemic junctions, however, the pulmonary venous junction appears later. Our experience shows that three-dimensional reconstructions have three advantages. First, they provide clear access to the combined morphological and molecular data, allowing clarification and verification of morphogenetic concepts for nonmorphological experts and setting the scene for further discussion. Second, they demonstrate that, from the outset, the myocardium surrounding the pulmonary veins is distinct from that clothing the systemic venoatrial junctions. Third, they reveal an anatomical and molecular continuity between the entrance of the systemic venous tributaries, the internodal atrial myocardium, and the atrioventricular region. All these regions are derived from primary myocardium, providing a molecular basis for the observed nonrandom distribution of focal right atrial tachycardias.

Animals↗
PubMed2004

Increased cardiac workload by closure of the ductus arteriosus leads to hypertrophy and apoptosis rather than to hyperplasia in the late fetal period.

It is generally thought that adult mammalian cardiomyocytes compensate for an increased workload by hypertrophy, whereas fetal myocardium grows by cellular proliferation. We analyzed the response of late-fetal rat hearts upon an increased workload imposed by premature constriction of the ductus arteriosus with indomethacin. Initially the fetal heart responds by proliferative growth, as both wet weight and labeling index (bromodeoxyuridine incorporation) of the ventricles increased, whereas neither a change in the fibroblast fraction, ploidy and nucleation in the ventricles is observed. However, this hyperplastic growth is abrogated by a subsequent burst in apoptosis and followed by a hypertrophic response as based on a decrease in DNA and increase in both RNA and protein concentration. This hypertrophic growth was accompanied by a 1.4-fold increase in the volume of the cardiomyocytes. Changes in the molecular phenotype characteristic of pressure-overload hypertrophic growth accompany the process. Thus, the levels of expression of beta-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of alpha-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change. In situ hybridization showed that the pattern of mRNA expression changed first in the right ventricular wall and subsequently in the left ventricular free wall as well. It is concluded that pressure-overload imposed on the late-fetal heart induces limited proliferative growth complemented by extensive hypertrophic growth.

Animals↗
PubMed2004

Lineage and morphogenetic analysis of the cardiac valves.

We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (alphaMHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.

Animals↗
PubMed2004

Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs.

Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from beta- to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) A, B, and C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism.

Animals↗
PubMed2004

The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart.

OBJECTIVE: The molecular mechanisms that regulate the formation of the conduction system are poorly understood. We studied the developmental expression pattern and functional aspects of the T-box transcription factor Tbx3, a novel marker for the murine central conduction system (CCS). METHODS: The patterns of expression of Tbx3, and of Cx40, Cx43, and Nppa, which are markers for atrial and ventricular chamber-type myocardium in the developing heart, were analyzed in mice by in situ hybridization and three-dimensional reconstruction analysis. The function of Tbx3 in regulating Nppa and Cx40 promoter activity was studied in vitro. RESULTS: In the formed heart, Tbx3 is expressed in the sinoatrial node (SAN), atrioventricular node (AVN), bundle and proximal bundle branches (BBs), as well as the internodal regions and the atrioventricular region. Throughout cardiac development, Tbx3 is expressed in an uninterrupted myocardial domain that extends from the sinoatrial node to the atrioventricular region. This expression domain is present in the looping heart tube from E8.5 onwards. Expression of the chamber-type myocardial markers is specifically absent from the Tbx3 expression domain. Tbx3 is able to repress Nppa and Cx40 promoter activity and abolish the synergistic activation of the Nppa promoter by Tbx5 and Nkx2.5. CONCLUSION: We identified the T-box transcription factor Tbx3 as a novel and accurate marker for the central conduction system. Our analysis implicates a role for Tbx3 in repressing a chamber-specific program of gene expression in regions from which the components of the central conduction system are subsequently formed.

Animals↗
PubMed2004

Dynamic patterns of expression of BMP isoforms 2, 4, 5, 6, and 7 during chicken heart development.

Bone morphogentic proteins (BMPs) play an important role in cardiac development. Using an in vitro explant analysis, we show that BMPs are crucial for myocardium formation. As a first approach to identify which BMP may be involved in myocardium formation in intra- and extracardiac mesenchyme in vivo, a survey of the expression patterns of BMP2, -4, -5, -6, and -7 mRNA is prepared by in situ hybridization in chicken embryonic hearts from HH5 to 44. During recruitment of mesodermal cells to the outflow tract myocardium (HH10-23), BMP2, -4, -5, and -7 mRNA are expressed in the distal myocardial border and the flanking mesenchyme. After completion, BMP2 and -4 mRNA become restricted to the mesenchyme and BMP5 and -7 mRNA to the myocardium. At the venous pole, BMP2, -5, and -7 mRNA are expressed in the distal myocardial border of the caval vein, while BMP2, -5, -6, and -7 mRNA are expressed in the distal myocardium around the pulmonary vein. BMP4 mRNA is expressed in the adjacent mesenchyme at both sides. During muscularization of the atrioventricular cushions and the tricuspid valve, the cardiomyocytes that protrude into the mesenchyme express BMP2, -4, -5, and -7 mRNA, whereas BMP6 mRNA is expressed in the cushion mesenchyme. The myocardial protrusions formed in the mesenchymal proximal outlet septum express BMP4, -5, and -7 mRNA, while BMP2 and -6 mRNA are expressed in the mesenchyme. The spatiotemporal expression patterns of these BMPs in relation to myocardium formation at the distal ends and within the heart suggest a role for BMPs in myocardium formation. During delamination of the valves, BMP4 and -6 mRNA are expressed at the ventricular side of the forming mitral valve, BMP4 mRNA at the ventricular side of the forming tricuspid valve, and BMP2, -4, and -6 mRNA at the vascular side of the forming semilunar valves.

Animals↗
PubMed2004

Expression of bone morphogenetic protein-10 mRNA during chicken heart development.

In this communication we describe the expression pattern of BMP10 mRNA during cardiac development in chickens. BMP10 is considered an important factor in the regulation of cardiac growth and trabeculation in the murine embryo. We identified chicken Ests, which are similar to mouse and human BMP10 in the UMIST database. The cDNA clone that contained most sequences was obtained, verified by sequence analysis, and used to determine the spatiotemporal pattern of gene expression. BMP10 mRNA is initially expressed at HH10 in the myocardium of the arterial pole of the heart tube, anterior to the interventricular groove. Between HH14 and HH22, BMP10 mRNA becomes broadly expressed in the outflow tract, the distal part of the inflow tract, and the trabeculated part of the developing ventricles and atria. From HH31 onward, BMP10 mRNA expression decreases in the ventricular myocardium by first disappearing from the compact myocardium and then from the tips of the trabecules. At HH44, BMP10 mRNA is expressed only in the trabeculated myocardium of the atria and the endocardium of the ventricles. The observed expression pattern of BMP10 mRNA suggests that it may play a role in regulating the formation of the ventricular wall and trabecules.

Animals↗
PubMed2004

Controversies concerning the anatomical definition of the conduction tissues.

Conduction across the atrioventricular junctions had long been controversial, with arguments raging as to whether such conduction was myogenic or neurogenic. The landmark study of Tawara in 1906 established the existence of an axis of histologically specialized myocardial cells contained within fibrous sheaths as being responsible for rapid conduction from the atrial to the ventricular myocardium. Keith and Flack then demonstrated that the atrial impulse was generated in the sinus node, with subsequent slowing within the atrioventricular node of Tawara. The detailed reviews of Aschoff and Monckeberg then emphasized the morphological features that permit unequivocal recognition of the nodes, along with rapidly conducting tracts. It is now pertinent that we remember these original criteria for anatomical recognition as we discuss the steps involved in the development of these conducting structures from their embryologic primordiums. In this review, we restate the criteria of Aschoff and Monckeberg, then discuss their relevance to the developmental issues, emphasizing that all myocardial cells have the potential to conduct. The important issues, therefore, are the changes that occur as the heart itself changes from a solitary muscular tube, already possessing the capacity t generate an electrocardiogram, to the four-chambered structure we recognize in postnatal life.

Animals↗
PubMed2004

Molecular imaging of the embryonic heart: Fables and facts on 3D imaging of gene expression patterns.

Molecular imaging, which is the three-dimensional (3D) visualization of gene expression patterns, is indispensable for the study of the function of genes in cardiac development. The instrumentation, as well as the development of specific contrast agents for molecular imaging, has shown spectacular advances in the last decade. In this review, the spatial resolutions, contrast agents, and applications of these imaging methods in the field of cardiac embryology are discussed. Apart from 3D reconstructions from histological sections, not many of these methods have been applied in embryological research. This review shows that, for most methods, neither the spatial resolutions nor the specificity and applicability of the contrast agents are adequate for the reliable imaging of specific gene expression at the microscopic resolution required for embryological studies of small organs like the developing heart. Although a 3D reconstruction from sections will always suffer from imperfections, the resulting reconstructions meet the aim of most biological studies, especially since the original microscopic images are linked. With respect to imaging of gene expression, only histological sections and laser scanning microscopy provide the required resolution and specificity at the tissue and cellular level. Episcopic fluorescence image capturing and optical projection tomography are being used for microscopic phenotyping and lineage analysis, and both show potential for detailed molecular imaging. Other methods can be used very efficiently in rapid evaluation of biological experiments and high-throughput screens of large-scale gene expression profiling efforts when high spatial resolution is not required.

Animals↗
PubMed2004

Making more heart muscle.

Postnatally, heart muscle cells almost completely lose their ability to divide, which makes their loss after trauma irreversible. Potential repair by cell grafting or mobilizing endogenous cells is of particular interest for possible treatments for heart disease, where the poor capacity for cardiomyocyte proliferation probably contributes to the irreversibility of heart failure. Knowledge of the molecular mechanisms that underly formation of heart muscle cells might provide opportunities to repair the diseased heart by induction of (trans) differentiation of endogenous or exogenous cells into heart muscle cells. We briefly review the molecular mechanisms involved in early development of the linear heart tube by differentiation of mesodermal cells into heart muscle cells. Because the initial heart tube does not comprise all the cardiac compartments present in the adult heart, heart muscle cells are added to the distal borders of the tube and within the tube. At both distal borders, mesodermal cell are recruited into the cardiac lineage and, within the heart tube, muscular septa are formed. In this review, the relative late additions of heart muscle cells to the linear heart tube are described and the potential underlying molecular mechanisms are discussed.

Animals↗
PubMed2004

T-box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers.

Specific regions of the embryonic heart tube differentiate into atrial and ventricular chamber myocardium, whereas the inflow tract, atrioventricular canal, inner curvatures, and outflow tract do not. These regions express Tbx2, a transcriptional repressor. Here, we tested its role in chamber formation. The temporal and spatial pattern of Tbx2 mRNA and protein expression in mouse hearts was found to be complementary to that of chamber myocardium-specific genes Nppa, Cx40, Cx43, and Chisel, and was conserved in human. In vitro, Tbx2 repressed the activity of regulatory fragments of Cx40, Cx43, and Nppa. Hearts of transgenic embryos that expressed Tbx2 in the prechamber myocardium completely failed to form chambers and to express the chamber myocardium-specific genes Nppa, Cx40, and Chisel, whereas other cardiac genes were normally expressed. These findings provide the first evidence that Tbx2 is a determinant in the local repression of chamber-specific gene expression and chamber differentiation.

Animals↗
PubMed2004

Regional expression of L-type calcium channel subunits during cardiac development.

The contraction of cardiomyocytes is initiated by the entrance of extracellular calcium through specific calcium channels. Within the myocardium, L-type calcium channels are most abundant. In the heart, the main pore-forming subunit is the alpha1C, although there is a larger heterogeneity on auxiliary beta subunits. We have analyzed the distribution pattern of different alpha1C and beta subunits during cardiac development by immunohistochemistry. We observed homogeneous expression of alpha1C and beta subunits within the early tubular heart, whereas regional differences are observed during the late embryogenesis. beta2 and beta4 show differential expression within the embryonic myocardium. alpha1CD1 displays only a transient enhanced expression in the ventricular conduction system. In adult heart, the expression of the different calcium channel subunits analyzed is homogeneous along the entire myocardium except for alpha1CD1 that is practically undetectable. These findings suggest that beta subunits might play a major role in conferring calcium handling heterogeneity within the developing embryonic myocardium, while alpha1C subunits might contribute just transiently.

Animals↗
PubMed2004

Architectural plan for the heart: early patterning and delineation of the chambers and the nodes.

During folding of the embryo, lateroanterior visceral mesoderm forms the embryonic tubular heart at the midline, just ventral to the foregut. In mice, this nascent tube contains the future left ventricle and atrioventricular canal. Mesenchymal cells subsequently recruited to the cardiac lineage at the intake and the outflow of the tube will form the atria and the right ventricle and outflow tract, respectively. Shortly after its emergence, the embryonic heart tube starts to loop, and the first signs of left ventricular chamber differentiation become visible on the outer curvature of the middle portion of the tube. Subsequently, the right ventricle differentiates cranially, and the atria caudally, while the inflow tract, atrioventricular canal, inner curvatures, and outflow tract form recognizable components flanking the chambers. The latter, nonchamber regions in turn provide signals for the formation of the cushion mesenchyme, are involved in remodeling of the heart, and form the nodes of the conduction system. This review discusses how the patterning of the heart tube relates to the localized differentiation of atrial and ventricular chambers, why some parts of the heart do not form chambers, and how this relates to the formation of the conduction system.

Animals↗