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Antoon F.m. Moorman - One of the best experts on this subject based on the ideXlab platform.
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Evolution and Development of the Atrial Septum
Anatomical record (Hoboken N.J. : 2007), 2018Co-Authors: Bjarke Jensen, Tobias Wang, Antoon F.m. MoormanAbstract:The complete division of the atrial cavity by a septum, resulting in a left and right atrium, is found in many amphibians and all amniotes (reptiles, birds, and mammals). Surprisingly, it is only in eutherian, or placental, mammals that full atrial septation necessitates addition from a second septum. The high incidence of incomplete closure of the atrial septum in human, so-called probe patency, suggests this manner of closure is inefficient. We review the evolution and development of the atrial septum to understand the peculiar means of forming the atrial septum in eutherian mammals. The most primitive atrial septum is found in lungfishes and comprises a myocardial component with a mesenchymal cap on its leading edge, reminiscent to the primary atrial septum of embryonic mammals before closure of the primary foramen. In reptiles, birds, and mammals, the primary foramen is closed by the mesenchymal tissues of the Atrioventricular Cushions, the dorsal mesenchymal protrusion, and the mesenchymal cap. These tissues are also found in lungfishes. The closure of the primary foramen is preceded by the development of secondary perforations in the septal myocardium. In all amniotes, with the exception of eutherian mammals, the secondary perforations do not coalesce to a secondary foramen. Instead, the secondary perforations persist and are sealed by myocardial and endocardial growth after birth or hatching. We suggest that the error-prone secondary foramen allows large volumes of oxygen-rich blood to reach the cardiac left side, needed to sustain the growth of the extraordinary large offspring that characterizes eutherian mammals. Anat Rec, 302:32-48, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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Two Distinct Pools of Mesenchyme Contribute to the Development of the Atrial Septum
Circulation research, 2006Co-Authors: Mathilda T.m. Mommersteeg, Robert H. Anderson, Maurice J.b. Van Den Hoff, Alexandre T. Soufan, Frederik J. De Lange, Vincent M. Christoffels, Antoon F.m. MoormanAbstract:Closure of the primary atrial foramen is achieved by fusion of the Atrioventricular Cushions with the mesenchymal cap on the leading edge of the muscular primary atrial septum. A fourth component involved is the vestibular spine, originally described by His in 1880 as an intra-cardiac continuation of the extra-cardiac mesenchyme of the dorsal mesocardium. The morphogenesis of this area is of great clinical interest, because of the high incidence of atrial and Atrioventricular septal defects. Nonetheless, the origin of the participating components is largely unknown. Here we report that the primary atrial foramen is surrounded in its entirety by mesenchyme derived from endocardium. A second population of mesenchyme not derived from endocardium was observed at the caudal margin of the mesenchymal atrial cap, entirely embedded within the mesenchyme derived from endocardium and contiguous with the mesenchyme of the dorsal mesocardium. Our reconstructions show this second population does indeed take the form of a short spine, albeit that it is the right pulmonary ridge, rather than this spine, that protrudes into the atrial lumen. From the stance of morphological description, therefore, there is little thus far to substantiate the existence of an atrial spine.
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Lineage and Morphogenetic Analysis of the Cardiac Valves
Circulation research, 2004Co-Authors: Frederik J. De Lange, Robert H. Anderson, Antoon F.m. Moorman, Maurice J.b. Van Den Hoff, Alexandre T. Soufan, Jörg Männer, Corrie De Gier-de Vries, Michael D. Schneider, Sandra Webb, Vincent M. ChristoffelsAbstract: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.
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Dynamic patterns of expression of BMP isoforms 2, 4, 5, 6, and 7 during chicken heart development.
The anatomical record. Part A Discoveries in molecular cellular and evolutionary biology, 2004Co-Authors: Semir Somi, Antoon F.m. Moorman, Anita A.m. Buffing, Maurice J.b. Van Den HoffAbstract: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.
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Cardiac Septation A Late Contribution of the Embryonic Primary Myocardium to Heart Morphogenesis
Circulation research, 2002Co-Authors: Wouter H. Lamers, Antoon F.m. MoormanAbstract:Heart morphogenesis comprises 2 major consecutive steps, viz. chamber formation followed by septation. Septation is the remodeling of the heart from a single-channel peristaltic pump to a dual-channel, synchronously contracting device with 1-way valves. In the human heart, septation occurs between 4 and 7 weeks of development. Cardiac looping and chamber formation bring the contributing structures into position to engage in septation. Cardiomyocytes that participate in chamber formation do not materially contribute to septation. The (re)discovery of the role of extracardiac mesenchymal tissue in Atrioventricular septation, the appreciation that the formation of the right Atrioventricular connection is more than a mere rightward expansion of the Atrioventricular canal, the awareness that myocardium originating from the so-called anterior heart field regresses after its function as outflow-tract sphincter ceases, and the recent finding that the myocardialized proximal portion of the outflow-tract septum becomes the supraventricular crest have all significantly enhanced our understanding of the morphogenetic processes that contribute to septation. The bifurcation of the ventricular conduction system is the landmark that separates the contribution of the Atrioventricular Cushions and the outflow-tract ridges to septation and that divides the muscular ventricular septum in inlet, trabecular, and outlet portions.
Robert E. Poelmann - One of the best experts on this subject based on the ideXlab platform.
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Embryonic human and adult elephant hearts.
2014Co-Authors: Robert E. Poelmann, Lambertus J. Wisse, Adriana Gittenberger-de C. Groot, Rebecca Vicente-steijn, Margot M. Bartelings, Sonja Everts, Tamara Hoppenbrouwers, Boudewijn P. T. Kruithof, Bjarke Jensen, Paul W. De BruinAbstract:(Fig. A, B) Epicardial cushion (*) in inner curvature between OFT and AVC. The inlet septum becomes apparent more apically (Fig. C). (D) and Fig S4 represent a reconstructed 7 mm embryo with folding and inlet septum formation. (F) 3D Comparison of development. Top row, 4 species showing relation of epicardial cushion (pink) with folding septum (dark blue). Bottom row, left lateral view, showing connection of folding septum with the inlet septum (light blue). The interventricular foramen connects left and right ventricle. In python this connection is represented by the cavum venosum. The AV myocardium is depicted in yellow and the various cushion tissues in green. (G, H) adult elephant heart (G) CT-image of first bifid elephant heart. (H) Anatomical dissection of the interventricular septum of the second heart. Left descending coronary artery (arrow) and the deep epicardial fat pad are outlined. Note the relative absence of a folding component. The dissected chordae tendineae of the tricuspid valve are visible in the lower part of Fig 5H. Abbrev. AVC Atrioventricular Cushions; FS folding septum; IS inlet septum; LV left ventricle; RV right ventricle; OFT outflow tract cushion.
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Septum formation in the mouse.
2014Co-Authors: Robert E. Poelmann, Lambertus J. Wisse, Adriana Gittenberger-de C. Groot, Rebecca Vicente-steijn, Margot M. Bartelings, Sonja Everts, Tamara Hoppenbrouwers, Boudewijn P. T. Kruithof, Bjarke Jensen, Paul W. De BruinAbstract:(A, B) Almost transverse sections of the same embryo showing WT1+ epicardial cells in the folding septum (FS,→) at ED 10.5, Fig. B is more apically located. (C, D) epicardial cells in FS of wildtype mouse at ED 12.5 and (E) present in the inlet septum underneath the posterior AV cushion. Note: WT1 staining of mesenchyme in septal OFT cushion is unrelated to epicardial cells. (F-H) Podoplanin mutant with diminutive PEO, presents with sparse epicardium lining the pericardial cavity (F, G) and with an underdeveloped septum lacking EPDCs in both FS (G) and inlet septum (IS) (H). (I-L) Immunostained for Tbx5 in a wild type mouse ED 14.5, four levels from anterior-posterior. (I) Tbx5 in LV trabeculations but not in the RV close to the outflow tract; core of septum is negative. (J-L) More posteriorly located sections, trabeculations in RV belonging to the inlet part become positive for Tbx5. (M-P) Four positions of a 3D Amira reconstruction of ED 10.5. The epicardial cushion in pink (*), the folding septum in dark blue and the inlet septum in light blue. Endocardial Cushions in green and the AVC myocardium in yellow. See also Fig. S3 for animated 3D. Abbrev. AVC Atrioventricular Cushions; FS folding septum; IS inlet septum; LV left ventricle; M mitral orifice; RV right ventricle; OFT outflow tract cushion; T tricuspid orifice, • interventricular communication, + septal band.
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Chicken embryo HH27.
2014Co-Authors: Robert E. Poelmann, Lambertus J. Wisse, Adriana Gittenberger-de C. Groot, Rebecca Vicente-steijn, Margot M. Bartelings, Sonja Everts, Tamara Hoppenbrouwers, Boudewijn P. T. Kruithof, Bjarke Jensen, Paul W. De BruinAbstract:Provides 6 sections of a serially sectioned chicken embryo (HH27) to demonstrate the merging of the folding and inlet components before septation is finished. From this embryo Fig 3D and Fig. S2 have been reconstructed. Similar series served as basis for the other species depicted in Fig S1, S3 and S4. Fig 6.A is most cranial, showing the epicardial cushion (*) at a level between outflow tract (OFT) and the right (RA) and left atria (LA) with the AV Cushions in between. The cranial cap of the left ventricle (LV) is grazed in the section. Fig 6.B and C give the cranial extension of the folding septum (FS) with the epicardial cushion (*) located between the outflow tract and the fused AV Cushions (AVC). Fig 6.D shows the FS bordering the interventricular foramen. It is evident that the core of the folding septum is lined on the left and right side by many trabeculations. Fig. 6.E The AV Cushions are attached to the flanks of the inlet septum where also the tip of the septal OFT cushion is found (arrow). The inlet (IS) and folding components have fused and constitute the floor of the interventricular foramen. Fig 6.E, F The right AV junction is present in the RV immediately above the arrow and can be traced upstream in Fig F and downstream in Fig. D. Note the close relationship to the IS. The folding septum becomes less compact and the trabeculations become more conspicuous. Abbrev. AVC Atrioventricular Cushions; FS folding septum; IS inlet septum; LA left atrium; LV left ventricle; RA right atrium; RV right ventricle; OFT outflow tract cushion with its proximal tip indicated by arrow in Fig. F.
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PDGF-B signaling is important for murine cardiac development: its role in developing Atrioventricular valves, coronaries, and cardiac innervation.
Developmental dynamics : an official publication of the American Association of Anatomists, 2008Co-Authors: Nynke M.s. Van Den Akker, Robert E. Poelmann, Leah C.j. Winkel, Maya H. Nisancioglu, Saskia Maas, Lambertus J. Wisse, Annika Armulik, Heleen Lie-venema, Christer Betsholtz, Adriana C. Gittenberger-de GrootAbstract:We hypothesized that PDGF-B/PDGFR-beta-signaling is important in the cardiac contribution of epicardium-derived cells and cardiac neural crest, cell lineages crucial for heart development. We analyzed hearts of different embryonic stages of both Pdgf-b-/- and Pdgfr-beta-/- mouse embryos for structural aberrations with an established causal relation to defective contribution of these cell lineages. Immunohistochemical staining for alphaSMA, periostin, ephrinB2, EphB4, VEGFR-2, Dll1, and NCAM was performed on wild-type and knockout embryos. We observed that knockout embryos showed perimembranous and muscular ventricular septal defects, maldevelopment of the Atrioventricular Cushions and valves, impaired coronary arteriogenesis, and hypoplasia of the myocardium and cardiac nerves. The abnormalities correspond with models in which epicardial development is impaired and with neuronal neural crest-related innervation deficits. This implies a role for PDGF-B/PDGFR-beta-signaling specifically in the contribution of these cell lineages to cardiac development.
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Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development.
TheScientificWorldJournal, 2007Co-Authors: Heleen Lie-venema, Robert E. Poelmann, Nynke M.s. Van Den Akker, Saskia Maas, Marco C. Deruiter, Noortje A.m. Bax, Elizabeth M. Winter, Tuija Kekarainen, Rob C. Hoeben, Adriana C. Gittenberger-de GrootAbstract:During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the Atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation. Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the Atrioventricular Cushions and the trabeculae. With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.
James F. Martin - One of the best experts on this subject based on the ideXlab platform.
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Tbx2 and Tbx3 induce Atrioventricular myocardial development and endocardial cushion formation
Cellular and Molecular Life Sciences, 2012Co-Authors: Reena Singh, Marianne Petry, M Sameer Rana, Phil Barnett, Henner F. Farin, Willem M. Hoogaars, Thomas Grieskamp, Henk Buermans, Todd Heallen, James F. MartinAbstract:A key step in heart development is the coordinated development of the Atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the Atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the Atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form Atrioventricular Cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the Cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development.
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Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into Atrioventricular Cushions.
Development (Cambridge England), 2002Co-Authors: Chengyu Liu, Wei Liu, Jennifer Palie, Nigel A. Brown, James F. MartinAbstract:Inactivation of the left-right asymmetry gene Pitx2 has been shown, in mice, to result in right isomerism with associated defects that are similar to that found in humans. We show that the Pitx2c isoform is expressed asymmetrically in a presumptive secondary heart field within the branchial arch and splanchnic mesoderm that contributes to the aortic sac and conotruncal myocardium. Pitx2c was expressed in left aortic sac mesothelium and in left splanchnic and branchial arch mesoderm near the junction of the aortic sac and branchial arch arteries. Mice with an isoform-specific deletion of Pitx2c had defects in asymmetric remodeling of the aortic arch vessels. Fatemapping studies using a Pitx2 cre recombinase knock-in allele showed that daughters of Pitx2 -expressing cells populated the right and left ventricles, Atrioventricular Cushions and valves and pulmonary veins. In Pitx2 mutant embryos, descendents of Pitx2 -expressing cells failed to contribute to the Atrioventricular Cushions and valves and the pulmonary vein, resulting in abnormal morphogenesis of these structures. Our data provide functional evidence that the presumptive secondary heart field, derived from branchial arch and splanchnic mesoderm, patterns the forming outflow tract and reveal a role for Pitx2c in aortic arch remodeling. Moreover, our findings suggest that a major function of the Pitx2 -mediated left right asymmetry pathway is to pattern the aortic arches, outflow tract and Atrioventricular valves and Cushions.
Andy Wessels - One of the best experts on this subject based on the ideXlab platform.
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The Role of the Epicardium in the Formation of the Cardiac Valves in the Mouse
Etiology and Morphogenesis of Congenital Heart Disease, 2016Co-Authors: Marie M. Lockhart, Maurice J.b. Van Den Hoff, Andy WesselsAbstract:In recent years, insights into the role of the epicardium in cardiac development have significantly changed. An important contribution to this increasing knowledge comes from the availability of mouse models that facilitate the study of the fate of the epicardial cell lineage and that allow epicardial-specific manipulation of expression of genes involved in regulation of epicardial cell behavior. In this contribution we will discuss our growing understanding of the role of the epicardium and epicardially derived cells in the formation of the Atrioventricular valve leaflets. We will illustrate how epicardially derived cells specifically contribute to the development of the leaflets that derive from the lateral Atrioventricular Cushions, and we will discuss the role of Bmp signaling, through the Bmp receptor BmpR1A/Alk3, in the regulation of the preferentially migration of EPDCs into the parietal AV valve leaflets.
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Epicardially-derived Fibroblasts Preferentially Contribute to the Parietal Leaflets of the Atrioventricular Valves in the Murine Heart
Developmental biology, 2012Co-Authors: Andy Wessels, Marie M. Lockhart, Maurice J.b. Van Den Hoff, Aimee L. Phelps, Richard F. Adamo, Kimberly Sauls, Laura E. Briggs, Russell A. Norris, Bram Van Wijk, José M. Pérez-pomaresAbstract:The importance of the epicardium for myocardial and valvuloseptal development has been well established; perturbation of epicardial development results in cardiac abnormalities, including thinning of the ventricular myocardial wall and malformations of the Atrioventricular valvuloseptal complex. To determine the spatiotemporal contribution of epicardially derived cells to the developing fibroblast population in the heart, we have used a mWt1/IRES/GFP-Cre mouse to trace the fate of EPDCs from embryonic day (ED)10 until birth. EPDCs begin to populate the compact ventricular myocardium around ED12. The migration of epicardially derived fibroblasts toward the interface between compact and trabecular myocardium is completed around ED14. Remarkably, epicardially derived fibroblasts do not migrate into the trabecular myocardium until after ED17. Migration of EPDCs into the Atrioventricular cushion mesenchyme commences around ED12. As development progresses, the number of EPDCs increases significantly, specifically in the leaflets which derive from the lateral Atrioventricular Cushions. In these developing leaflets the epicardially derived fibroblasts eventually largely replace the endocardially derived cells. Importantly, the contribution of EPDCs to the leaflets derived from the major AV Cushions is very limited. The differential contribution of EPDCs to the various leaflets of the Atrioventricular valves provides a new paradigm in valve development and could lead to new insights into the pathogenesis of abnormalities that preferentially affect individual components of this region of the heart. The notion that there is a significant difference in the contribution of epicardially and endocardially derived cells to the individual leaflets of the Atrioventricular valves has also important pragmatic consequences for the use of endocardial and epicardial cre-mouse models in studies of heart development.
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A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development
Developmental dynamics : an official publication of the American Association of Anatomists, 2007Co-Authors: Brian S. Snarr, Elaine E. Wirrig, Aimee L. Phelps, Thomas C. Trusk, Andy WesselsAbstract:The mesenchymal tissues involved in cardiac septation are derived from different sources. In addition to endocardial-derived mesenchyme, the heart also receives contributions from the neural crest, the proepicardium, and the dorsal mesenchymal protrusion (DMP). Whereas the contributions of the neural crest and proepicardium have been thoroughly studied, the DMP has received little attention. Here, we present the results of a comprehensive spatiotemporal study of the DMP in cardiac development. Using the Tie2-Cre mouse, immunohistochemistry, and AMIRA reconstructions, we show that the DMP, in combination with the mesenchymal cap on the primary atrial septum, fuse with the major Atrioventricular Cushions to close the primary atrial foramen and to form the Atrioventricular mesenchymal complex. In this complex, the DMP constitutes a discrete prominent mesenchymal component, wedged in between the major Cushions. This new model for Atrioventricular septation may provide novel insights into understanding the etiology of congenital cardiac malformations.
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The Development of the Atrioventricular Junction in the Human Heart
Circulation research, 1996Co-Authors: Andy Wessels, Robert H. Anderson, M.w.m. Markman, J.l.m. Vermeulen, Antoon F.m. Moorman, W.h. LamersAbstract:The histogenesis of the separation between atrial and ventricular myocardium at the Atrioventricular junction in the developing human heart has been investigated immunohistochemically by using monoclonal antibodies specific for Atrioventricular cushion tissue, mesenchymal cells, atrial and ventricular myocardium, and myocardium of the primary ring. It was found that the insulation between the muscle masses of atrium and ventricle is established by the fusion of the tissues of the Atrioventricular sulcus (located at the epicardial side of the junctional myocardium) with those of the Atrioventricular Cushions (located at the endocardial side of the junctional myocardium). This process takes place at the ventricular margin of the myocardium of the Atrioventricular canal. The separation of atrial and ventricular myocardium starts at approximately 7 weeks of development in the anteromedial portion of the right Atrioventricular junction and is largely completed around the 12th week of development. The only remaining myocardial continuity between atrial and ventricular myocardium is the Atrioventricular axis of conduction. Our findings show that the nonmuscular part of the developing leaflets of the Atrioventricular valves derives from the Atrioventricular Cushions and that the tissues of the Atrioventricular groove do not contribute to the development of these leaflets.
Robert H. Anderson - One of the best experts on this subject based on the ideXlab platform.
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Development of the atrial septum in relation to postnatal anatomy and interatrial communications
Heart (British Cardiac Society), 2016Co-Authors: Bjarke Jensen, Diane E. Spicer, Mary N. Sheppard, Robert H. AndersonAbstract:The atrial septum is probe patent in some 30% of the population, and is prone to have overt defects. Atrial septation is the coming together of several myocardial structures and mesenchymal tissues of intracardiac and extracardiac origin that must change identity to myocardium. We propose that the propensity for malformation of the atrial septum reflects this complicated morphogenesis. The morphogenesis of the atrial septum initiates from a ridge of mesenchyme, only a few hundred micrometres long, in the roof of the undivided atrial cavity. By growth of the myocardial primary septum, the mesenchymal ridge will be approximated to, and ultimately fuse, with the mesenchyme of the Atrioventricular Cushions. This fusion also takes in the so-called vestibular spine, and serves to close the primary atrial foramen. Interatrial communication is maintained by the development of perforations in the myocardial septum that will coalesce to produce the secondary foramen. Late in gestation, an infolding of the right atrial roof, previously identified as the secondary septum, will come to form the roof of the secondary foramen. Muscularisation of the mesenchymal ridge and vestibular spine serves to reinforce the attachment of the primary muscular septum to the Atrioventricular insulating plane, with the muscularised components, and the cranial infolding, then producing the rims of the oval fossa as seen in the postnatal heart. We show that other lesions that produce the potential for interatrial shunting are outside the confines of the atrial septum, and hence are best considered as interatrial communications, rather than 'atrial septal defects'.
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HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3
PLOS ONE, 2016Co-Authors: D. J. H. Dilg, Peter J. Scambler, Rasha Noureldin M. Saleh, Sarah Elizabeth Lee Phelps, Yoann Rose, Laurent Dupays, Cian Murphy, Timothy J. Mohun, Robert H. Anderson, Ariane ChapgierAbstract:Chromatin remodelling is essential for cardiac development. Interestingly, the role of histone chaperones has not been investigated in this regard. HIRA is a member of the HUCA (HIRA/UBN1/CABIN1/ASF1a) complex that deposits the variant histone H3.3 on chromatin independently of replication. Lack of HIRA has general effects on chromatin and gene expression dynamics in embryonic stem cells and mouse oocytes. Here we describe the conditional ablation of Hira in the cardiogenic mesoderm of mice. We observed surface oedema, ventricular and atrial septal defects and embryonic lethality. We identified dysregulation of a subset of cardiac genes, notably upregulation of troponins Tnni2 and Tnnt3, involved in cardiac contractility and decreased expression of Epha3, a gene necessary for the fusion of the muscular ventricular septum and the Atrioventricular Cushions. We found that HIRA binds GAGA rich DNA loci in the embryonic heart, and in particular a previously described enhancer of Tnni2/Tnnt3 (TTe) bound by the transcription factor NKX2.5. HIRA-dependent H3.3 enrichment was observed at the TTe in embryonic stem cells (ESC) differentiated toward cardiomyocytes in vitro. Thus, we show here that HIRA has locus-specific effects on gene expression and that histone chaperone activity is vital for normal heart development, impinging on pathways regulated by an established cardiac transcription factor.
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Two Distinct Pools of Mesenchyme Contribute to the Development of the Atrial Septum
Circulation research, 2006Co-Authors: Mathilda T.m. Mommersteeg, Robert H. Anderson, Maurice J.b. Van Den Hoff, Alexandre T. Soufan, Frederik J. De Lange, Vincent M. Christoffels, Antoon F.m. MoormanAbstract:Closure of the primary atrial foramen is achieved by fusion of the Atrioventricular Cushions with the mesenchymal cap on the leading edge of the muscular primary atrial septum. A fourth component involved is the vestibular spine, originally described by His in 1880 as an intra-cardiac continuation of the extra-cardiac mesenchyme of the dorsal mesocardium. The morphogenesis of this area is of great clinical interest, because of the high incidence of atrial and Atrioventricular septal defects. Nonetheless, the origin of the participating components is largely unknown. Here we report that the primary atrial foramen is surrounded in its entirety by mesenchyme derived from endocardium. A second population of mesenchyme not derived from endocardium was observed at the caudal margin of the mesenchymal atrial cap, entirely embedded within the mesenchyme derived from endocardium and contiguous with the mesenchyme of the dorsal mesocardium. Our reconstructions show this second population does indeed take the form of a short spine, albeit that it is the right pulmonary ridge, rather than this spine, that protrudes into the atrial lumen. From the stance of morphological description, therefore, there is little thus far to substantiate the existence of an atrial spine.
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Lineage and Morphogenetic Analysis of the Cardiac Valves
Circulation research, 2004Co-Authors: Frederik J. De Lange, Robert H. Anderson, Antoon F.m. Moorman, Maurice J.b. Van Den Hoff, Alexandre T. Soufan, Jörg Männer, Corrie De Gier-de Vries, Michael D. Schneider, Sandra Webb, Vincent M. ChristoffelsAbstract: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.
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The Development of the Atrioventricular Junction in the Human Heart
Circulation research, 1996Co-Authors: Andy Wessels, Robert H. Anderson, M.w.m. Markman, J.l.m. Vermeulen, Antoon F.m. Moorman, W.h. LamersAbstract:The histogenesis of the separation between atrial and ventricular myocardium at the Atrioventricular junction in the developing human heart has been investigated immunohistochemically by using monoclonal antibodies specific for Atrioventricular cushion tissue, mesenchymal cells, atrial and ventricular myocardium, and myocardium of the primary ring. It was found that the insulation between the muscle masses of atrium and ventricle is established by the fusion of the tissues of the Atrioventricular sulcus (located at the epicardial side of the junctional myocardium) with those of the Atrioventricular Cushions (located at the endocardial side of the junctional myocardium). This process takes place at the ventricular margin of the myocardium of the Atrioventricular canal. The separation of atrial and ventricular myocardium starts at approximately 7 weeks of development in the anteromedial portion of the right Atrioventricular junction and is largely completed around the 12th week of development. The only remaining myocardial continuity between atrial and ventricular myocardium is the Atrioventricular axis of conduction. Our findings show that the nonmuscular part of the developing leaflets of the Atrioventricular valves derives from the Atrioventricular Cushions and that the tissues of the Atrioventricular groove do not contribute to the development of these leaflets.