Publications by authors named "Jörg Männer"

41 Publications

On the Cardiac Loop and Its Failing: Left Ventricular Outflow Tract Obstruction.

J Am Heart Assoc 2020 02 28;9(3):e014857. Epub 2020 Jan 28.

Adult Congenital Heart Disease Program New York University School of Medicine New York NY.

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http://dx.doi.org/10.1161/JAHA.119.014857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033877PMC
February 2020

Spontaneous Left Cardiac Isomerism in Chick Embryos: Case Report, Review of the Literature, and Possible Significance for the Understanding of Ventricular Non-Compaction Cardiomyopathy in the Setting of Human Heterotaxy Syndromes.

Authors:
Jörg Männer

J Cardiovasc Dev Dis 2019 Nov 8;6(4). Epub 2019 Nov 8.

Group Cardio-Embryology, Institute of Anatomy and Embryology UMG, Georg August University Göttingen, D-37075 Göttingen, Germany.

The outer shape of most vertebrates is normally characterized by bilateral symmetry. The inner organs, on the other hand, are normally arranged in bilaterally asymmetric patterns. Congenital deviations from the normal organ asymmetry can occur in the form of mirror imagery of the normal arrangement (situs inversus), or in the form of arrangements that have the tendency for the development of bilateral symmetry, either in a pattern of bilateral left-sidedness (left isomerism) or bilateral right-sidedness (right isomerism). The latter two forms of visceral situs anomalies are called "heterotaxy syndromes". During the past 30 years, remarkable progress has been made in uncovering the genetic etiology of heterotaxy syndromes. However, the pathogenetic mechanisms causing the spectrum of cardiovascular defects found in these syndromes remain poorly understood. In the present report, a spontaneous case of left cardiac isomerism found in an HH-stage 23 chick embryo is described. The observations made in this case confirmed the existence of molecular isomerism in the ventricular chambers previously noted in mouse models. They, furthermore, suggest that hearts with left cardiac isomerism may have the tendency for the development of non-compaction cardiomyopathy caused by defective development of the proepicardium.
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http://dx.doi.org/10.3390/jcdd6040040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955803PMC
November 2019

Morphogenetic control of zebrafish cardiac looping by Bmp signaling.

Development 2019 11 14;146(22). Epub 2019 Nov 14.

Institute of Molecular Biology, Hannover Medical School, D-30625 Hannover, Germany

Cardiac looping is an essential and highly conserved morphogenetic process that places the different regions of the developing vertebrate heart tube into proximity of their final topographical positions. High-resolution 4D live imaging of mosaically labelled cardiomyocytes reveals distinct cardiomyocyte behaviors that contribute to the deformation of the entire heart tube. Cardiomyocytes acquire a conical cell shape, which is most pronounced at the superior wall of the atrioventricular canal and contributes to S-shaped bending. Torsional deformation close to the outflow tract contributes to a torque-like winding of the entire heart tube between its two poles. Anisotropic growth of cardiomyocytes based on their positions reinforces S-shaping of the heart. During cardiac looping, bone morphogenetic protein pathway signaling is strongest at the future superior wall of the atrioventricular canal. Upon pharmacological or genetic inhibition of bone morphogenetic protein signaling, myocardial cells at the superior wall of the atrioventricular canal maintain cuboidal cell shapes and S-shaped bending is impaired. This description of cellular rearrangements and cardiac looping regulation may also be relevant for understanding the etiology of human congenital heart defects.
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http://dx.doi.org/10.1242/dev.180091DOI Listing
November 2019

Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival.

Cardiovasc Res 2020 03;116(3):592-604

Department of Cardiology and Pulmonology, Georg-August University, Robert-Koch Str. 40, 37075 Göttingen, Germany.

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation.

Methods And Results: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis.

Conclusion: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.
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http://dx.doi.org/10.1093/cvr/cvz177DOI Listing
March 2020

Functional Morphology of the Cardiac Jelly in the Tubular Heart of Vertebrate Embryos.

J Cardiovasc Dev Dis 2019 02 27;6(1). Epub 2019 Feb 27.

Department of Cardiac Sciences, King Abdulaziz Cardiac Center, Section of Pediatric Cardiology, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia.

The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between the myocardium and endocardium, called "cardiac jelly" (CJ). During the past decades, research on CJ has mainly focused on its molecular and cellular biological aspects. This review focuses on the morphological and biomechanical aspects of CJ. Special attention is given to (1) the spatial distribution and fiber architecture of CJ; (2) the morphological dynamics of CJ during the cardiac cycle; and (3) the removal/remodeling of CJ during advanced heart looping stages, which leads to the formation of ventricular trabeculations and endocardial cushions. CJ acts as a hydraulic skeleton, displaying striking structural and functional similarities with the mesoglea of jellyfish. CJ not only represents a filler substance, facilitating end-systolic occlusion of the embryonic heart lumen. Its elastic components antagonize the systolic deformations of the heart wall and thereby power the refilling phase of the ventricular tube. Non-uniform spatial distribution of CJ generates non-circular cross sections of the opened endocardial tube (initially elliptic, later deltoid), which seem to be advantageous for valveless pumping. Endocardial cushions/ridges are cellularized remnants of non-removed CJ.
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http://dx.doi.org/10.3390/jcdd6010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463132PMC
February 2019

A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A.

Sci Rep 2019 02 27;9(1):2959. Epub 2019 Feb 27.

Institute of Molecular Biology, Hannover Medical School, D-30625, Hannover, Germany.

The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aa within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.
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http://dx.doi.org/10.1038/s41598-019-39648-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393482PMC
February 2019

Kinking and Torsion Can Significantly Improve the Efficiency of Valveless Pumping in Periodically Compressed Tubular Conduits. Implications for Understanding of the Form-Function Relationship of Embryonic Heart Tubes.

J Cardiovasc Dev Dis 2017 Nov 19;4(4). Epub 2017 Nov 19.

Group Cardio-Embryology, Institute of Anatomy and Embryology, UMG, Georg-August-University Goettingen, D-37075 Goettingen, Germany.

Valveless pumping phenomena (peristalsis, Liebau-effect) can generate unidirectional fluid flow in periodically compressed tubular conduits. Early embryonic hearts are tubular conduits acting as valveless pumps. It is unclear whether such hearts work as peristaltic or Liebau-effect pumps. During the initial phase of its pumping activity, the originally straight embryonic heart is subjected to deforming forces that produce bending, twisting, kinking, and coiling. This deformation process is called cardiac looping. Its function is traditionally seen as generating a configuration needed for establishment of correct alignments of pulmonary and systemic flow pathways in the mature heart of lung-breathing vertebrates. This idea conflicts with the fact that cardiac looping occurs in all vertebrates, including gill-breathing fishes. We speculate that looping morphogenesis may improve the efficiency of valveless pumping. To test the physical plausibility of this hypothesis, we analyzed the pumping performance of a Liebau-effect pump in straight and looped (kinked) configurations. Compared to the straight configuration, the looped configuration significantly improved the pumping performance of our pump. This shows that looping can improve the efficiency of valveless pumping driven by the Liebau-effect. Further studies are needed to clarify whether this finding may have implications for understanding of the form-function relationship of embryonic hearts.
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http://dx.doi.org/10.3390/jcdd4040019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753120PMC
November 2017

Blechschmidt Collection: Revisiting specimens from a historical collection of serially sectioned human embryos and fetuses using modern imaging techniques.

Congenit Anom (Kyoto) 2018 Sep 22;58(5):152-157. Epub 2018 Jan 22.

Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Along with the Carnegie Collection in the United States and the Kyoto Collection in Japan, the Blechschmidt Collection (Georg-August-University of Göttingen, Germany) is a major historical human embryo and fetus collection. These collections are of enormous value to human embryology; however, due to the nature of the historical histological specimens, some stains are fading in color, and some glass slides are deteriorating over time. To protect these specimens against such degradation and ensure their future usefulness, we tried to apply modern image scanning and computational reconstruction. Samples of histological specimens of the Blechschmidt Collection were digitized into images using commercial flatbed scanners with a resolution of 4800 pixels per inch. Two specimens were reconstructed into three-dimensional (3D) images by using modern techniques to vertically stack two-dimensional images of the slices into 3D blocks. The larger specimen of crown-rump length (CRL) 64.0 mm, a series of very large histological sections in human embryology, was reconstructed clearly, with its central nervous system segmented before stacking. The smaller specimen of CRL 17.5 mm was also reconstructed into 3D images. The outer surface of the embryo was intact, and its development was classified according to the widely used Carnegie stages (CSs). The CS of the specimen was identified as the later half of CS 20. The invaluable Blechschmidt Collection can be revisited for further research with modern techniques such as digital image scanning and computational 3D reconstruction.
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http://dx.doi.org/10.1111/cga.12261DOI Listing
September 2018

Use of the Coelomic Grafting Technique for Prolonged ex utero Cultivation of Late Preprimitive Streak-Stage Rabbit Embryos.

Cells Tissues Organs 2016 11;202(5-6):329-342. Epub 2016 Aug 11.

Due to its morphological similarity with the early human embryo, the pregastrulation-stage rabbit may represent an appropriate mammalian model for studying processes involved in early human development. The usability of mammalian embryos for experimental studies depends on the availability of whole embryo culture methods facilitating prolonged ex utero development. While currently used culture methods yield high success rates for embryos from primitive streak stages onward, the success rate of extended cultivation of preprimitive streak-stage mammalian embryos is low for all previously established methods and for all studied species. This limits the usability of preprimitive streak-stage rabbit embryos in experimental embryology. We have tested whether the extraembryonic coelom of 4-day-old chick embryos may be used for prolonged ex utero culture of preprimitive streak-stage rabbit embryos (stage 2, 6.2 days post coitum). We found that, within this environment, stage 2 rabbit blastocysts can be cultured at decreasing success rates (55% after 1 day, 35% after 2 days, 15% after 3 days) up to a maximum of 72 h. Grafted blastocysts can continue development from the onset of gastrulation to early organogenesis and thereby form all structures characterizing age-matched controls (e.g. neural tube, somites, beating heart). Compared to normal controls, successfully cultured embryos developed at a slower rate and finally showed some structural and gross morphological anomalies. The method presented here was originally developed for whole embryo culture of mouse embryos by Gluecksohn-Schoenheimer in 1941. It is a simple and inexpensive method that may represent a useful extension to presently available ex utero culture systems for rabbit embryos.
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http://dx.doi.org/10.1159/000446820DOI Listing
May 2017

The Digestive Tract and Derived Primordia Differentiate by Following a Precise Timeline in Human Embryos Between Carnegie Stages 11 and 13.

Anat Rec (Hoboken) 2016 Apr 30;299(4):439-49. Epub 2016 Jan 30.

Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto.

The precise mechanisms through which the digestive tract develops during the somite stage remain undefined. In this study, we examined the morphology and precise timeline of differentiation of digestive tract-derived primordia in human somite-stage embryos. We selected 37 human embryos at Carnegie Stage (CS) 11-CS13 (28-33 days after fertilization) and three-dimensionally analyzed the morphology and positioning of the digestive tract and derived primordia in all samples, using images reconstructed from histological serial sections. The digestive tract was initially formed by a narrowing of the yolk sac, and then several derived primordia such as the pharynx, lung, stomach, liver, and dorsal pancreas primordia differentiated during CS12 (21-29 somites) and CS13 (≥ 30 somites). The differentiation of four pairs of pharyngeal pouches was complete in all CS13 embryos. The respiratory primordium was recognized in ≥ 26-somite embryos and it flattened and then branched at CS13. The trachea formed and then elongated in ≥ 35-somite embryos. The stomach adopted a spindle shape in all ≥ 34-somite embryos, and the liver bud was recognized in ≥ 27-somite embryos. The dorsal pancreas appeared as definitive buddings in all but three CS13 embryos, and around these buddings, the small intestine bent in ≥ 33-somite embryos. In ≥ 35-somite embryos, the small intestine rotated around the cranial-caudal axis and had begun to form a primitive intestinal loop, which led to umbilical herniation. These data indicate that the digestive tract and derived primordia differentiate by following a precise timeline and exhibit limited individual variations.
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http://dx.doi.org/10.1002/ar.23314DOI Listing
April 2016

Cardiac looping may be driven by compressive loads resulting from unequal growth of the heart and pericardial cavity. Observations on a physical simulation model.

Front Physiol 2014 4;5:112. Epub 2014 Apr 4.

Group Cardio-Embryology, Institute for Anatomy and Embryology, UMG, Georg-August-University of Göttingen Göttingen, Germany.

The transformation of the straight embryonic heart tube into a helically wound loop is named cardiac looping. Such looping is regarded as an essential process in cardiac morphogenesis since it brings the building blocks of the developing heart into an approximation of their definitive topographical relationships. During the past two decades, a large number of genes have been identified which play important roles in cardiac looping. However, how genetic information is physically translated into the dynamic form changes of the looping heart is still poorly understood. The oldest hypothesis of cardiac looping mechanics attributes the form changes of the heart loop (ventral bending → simple helical coiling → complex helical coiling) to compressive loads resulting from growth differences between the heart and the pericardial cavity. In the present study, we have tested the physical plausibility of this hypothesis, which we call the growth-induced buckling hypothesis, for the first time. Using a physical simulation model, we show that growth-induced buckling of a straight elastic rod within the confined space of a hemispherical cavity can generate the same sequence of form changes as observed in the looping embryonic heart. Our simulation experiments have furthermore shown that, under bilaterally symmetric conditions, growth-induced buckling generates left- and right-handed helices (D-/L-loops) in a 1:1 ratio, while even subtle left- or rightward displacements of the caudal end of the elastic rod at the pre-buckling state are sufficient to direct the buckling process toward the generation of only D- or L-loops, respectively. Our data are discussed with respect to observations made in biological "models." We conclude that compressive loads resulting from unequal growth of the heart and pericardial cavity play important roles in cardiac looping. Asymmetric positioning of the venous heart pole may direct these forces toward a biased generation of D- or L-loops.
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http://dx.doi.org/10.3389/fphys.2014.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983514PMC
April 2014

Isolated left common carotid artery arising from the main pulmonary artery: where is the ductus arteriosus? an embryologist's view.

Authors:
Jörg Männer

World J Pediatr Congenit Heart Surg 2013 Oct;4(4):460-1

Group Cardio-Embryology, Institute for Anatomy and Embryology, UMG, Georg-August- University of Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1177/2150135113502058DOI Listing
October 2013

Respiratory distress and early neonatal lethality in Hspa4l/Hspa4 double-mutant mice.

Am J Respir Cell Mol Biol 2014 Apr;50(4):817-24

1 Institute of Human Genetics, and.

Heat shock proteins HSPA4L and HSPA4 are closely related members of the HSP110 family and act as cochaperones. We generated Hspa4l(-/-)Hspa4(-/-) mice to investigate a functional complementarity between HSPA4L and HSPA4 during embryonic development. Hspa4l(-/-)Hspa4(-/-) embryos exhibited marked pulmonary hypoplasia and neonatal death. Compared with lungs of wild-type, Hspa4l(-/-), and Hspa4(-/-) embryos, Hspa4l(-/-)Hspa4(-/-) lungs were characterized by diminished saccular spaces and increased mesenchymal septa. Mesenchymal hypercellularity was determined to be due to an increased cell proliferation index and decreased cell death. A significant increase in expression levels of prosurvival protein B cell leukemia/lymphoma 2 may be the cause for inhibition of apoptotic process in lungs of Hspa4(-/-)Hspa4l(-/-) embryos. Accumulation of glycogen and diminished expression of surfactant protein B, prosurfactant protein C, and aquaporin 5 in saccular epithelium suggested impaired maturation of type II and type I pneumocytes in the Hspa4l(-/-)Hspa4(-/-) lungs. Further experiments showed a significant accumulation of ubiquitinated proteins in the lungs of Hspa4l(-/-)Hspa4(-/-) embryos, indicating an impaired chaperone activity. Our study demonstrates that HSPA4L and HSPA4 collaborate in embryonic lung maturation, which is necessary for adaptation to air breathing at birth.
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http://dx.doi.org/10.1165/rcmb.2013-0132OCDOI Listing
April 2014

On the form problem of embryonic heart loops, its geometrical solutions, and a new biophysical concept of cardiac looping.

Authors:
Jörg Männer

Ann Anat 2013 Jul 18;195(4):312-323. Epub 2013 Mar 18.

Department of Anatomy and Embryology, Georg-August-University of Göttingen, Germany. Electronic address:

Background: Cardiac looping is an essential process in the morphogenesis of embryonic hearts. Unfortunately, relatively little is known about the form and biophysics of embryonic heart loops. Thompson regarded the form of an object as "a 'diagram of forces' … from it we can … deduce the forces that are acting or have acted upon it." Therefore, the present study was conducted to uncover the best geometrical solution of the form problem of embryonic heart loops. This approach may help to identify the biophysics of cardiac looping.

Results: Analysis of the tendrils of climbing plants disclosed striking resemblance between the configurations of embryonic heart loops and a form motif named helical perversion. Helical perversion occurs in helically wound objects where they connect two helical segments of opposite handedness (two-handed helix). Helical perversion evolves in living and non-living filamentary objects such as the tendrils of climbing plants and helical telephone cords.

Conclusions: Helical perversion may be the best geometrical solution of the form problem of embryonic heart loops. The dynamics and mechanics of the emergence of helical perversions are relatively well known. The behavior of looping embryonic hearts may be interpreted in light of this knowledge.
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http://dx.doi.org/10.1016/j.aanat.2013.02.008DOI Listing
July 2013

Integration of an optical coherence tomography (OCT) system into an examination incubator to facilitate in vivo imaging of cardiovascular development in higher vertebrate embryos under stable physiological conditions.

Ann Anat 2011 Oct 13;193(5):425-35. Epub 2011 May 13.

Department of Pediatric Cardiology and Intensive Care Medicine, Hannover Medical School, Germany.

High-resolution in vivo imaging of higher vertebrate embryos over short or long time periods under constant physiological conditions is a technically challenging task for researchers working on cardiovascular development. In chick embryos, for example, various studies have shown that without appropriate maintenance of temperature, as one of the main environmental factors, the embryonic heart rate drops rapidly and often results in an increase in regurgitant flow. Hemodynamic parameters are critical stimuli for cardiovascular development that, for a correct evaluation of their developmental significance, should be documented under physiological conditions. However, previous studies were mostly carried out outside of an incubator or under suboptimal environmental conditions. Here we present, to the best of our knowledge, the first detailed description of an optical coherence tomography (OCT) system integrated into an examination incubator to facilitate real-time in vivo imaging of cardiovascular development under physiological environmental conditions. We demonstrate the suitability of this OCT examination incubator unit for use in cardiovascular development studies by examples of proof of principle experiments. We, furthermore, point out the need for use of examination incubators for physiological OCT examinations by documenting the effects of room climate (22°C) on the performance of the cardiovascular system of chick embryos (HH-stages 16/17). Upon exposure to room climate, chick embryos showed a fast drop in the heart rate and striking changes in the cardiac contraction behaviour and the blood flow through the vitelline circulation. We have documented these changes for the first time by M-mode OCT and Doppler M-mode OCT.
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http://dx.doi.org/10.1016/j.aanat.2011.04.006DOI Listing
October 2011

Development of the venous pole of the heart in the frog Xenopus laevis: a morphological study with special focus on the development of the venoatrial connections.

Dev Dyn 2011 Jun 24;240(6):1518-27. Epub 2011 Mar 24.

Department of Anatomy and Embryology, Georg-August University of Göttingen, Göttingen, Germany.

The heart of lung-breathing vertebrates normally shows an asymmetric arrangement of its venoatrial connections along the left-right (L-R) body axis. The systemic venous tributaries empty into the right atrium while the pulmonary venous tributaries empty into the left atrium. The ways by which this asymmetry evolves from the originally symmetrically arranged embryonic venous heart pole are poorly defined. Here we document the development of the venous heart pole in Xenopus laevis (stages 40-46). We show that, prior to the appearance of the mouth of the common pulmonary vein (MCPV), the systemic venous tributaries empty into a bilaterally symmetric chamber (sinus venosus) that is demarcated from the developing atriums by a circular ridge of tissue (sinu-atrial ridge). A solitary MCPV appears during stage 41. From the time point of its first appearance onwards, the MCPV lies cranial to the sinu-atrial ridge and to the left of the developing interatrial septum and body midline. L-R lineage analysis shows that the interatrial septum and MCPV both derive from the left body half. The CPV, therefore, opens from the beginning into the future left atrium. The definitive venoatrial connections are established by the formation of a septal complex that divides the lumen of the venous heart pole into systemic and pulmonary venous flow pathways. This complex arises from the anlage of the interatrial septum and the left half of the sinu-atrial ridge.
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http://dx.doi.org/10.1002/dvdy.22611DOI Listing
June 2011

Germ layer differentiation during early hindgut and cloaca formation in rabbit and pig embryos.

J Anat 2010 Dec 28;217(6):665-78. Epub 2010 Sep 28.

Department of Anatomy and Embryology, Göttingen University, Göttingen, Germany.

Relative to recent advances in understanding molecular requirements for endoderm differentiation, the dynamics of germ layer morphology and the topographical distribution of molecular factors involved in endoderm formation at the caudal pole of the embryonic disc are still poorly defined. To discover common principles of mammalian germ layer development, pig and rabbit embryos at late gastrulation and early neurulation stages were analysed as species with a human-like embryonic disc morphology, using correlative light and electron microscopy. Close intercellular contact but no direct structural evidence of endoderm formation such as mesenchymal-epithelial transition between posterior primitive streak mesoderm and the emerging posterior endoderm were found. However, a two-step process closely related to posterior germ layer differentiation emerged for the formation of the cloacal membrane: (i) a continuous mesoderm layer and numerous patches of electron-dense flocculent extracellular matrix mark the prospective region of cloacal membrane formation; and (ii) mesoderm cells and all extracellular matrix including the basement membrane are lost locally and close intercellular contact between the endoderm and ectoderm is established. The latter process involves single cells at first and then gradually spreads to form a longitudinally oriented seam-like cloacal membrane. These gradual changes were found from gastrulation to early somite stages in the pig, whereas they were found from early somite to mid-somite stages in the rabbit; in both species cloacal membrane formation is complete prior to secondary neurulation. The results highlight the structural requirements for endoderm formation during development of the hindgut and suggest new mechanisms for the pathogenesis of common urogenital and anorectal malformations.
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http://dx.doi.org/10.1111/j.1469-7580.2010.01303.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039179PMC
December 2010

How does the tubular embryonic heart work? Looking for the physical mechanism generating unidirectional blood flow in the valveless embryonic heart tube.

Dev Dyn 2010 Apr;239(4):1035-46

Department of Anatomy and Cell Biology, Georg-August-University of Göttingen, D-37075 Göttingen, Germany.

The heart is the first organ to function in vertebrate embryos. The human heart, for example, starts beating around the 21st embryonic day. During the initial phase of its pumping action, the embryonic heart is seen as a pulsating blood vessel that is built up by (1) an inner endothelial tube lacking valves, (2) a middle layer of extracellular matrix, and (3) an outer myocardial tube. Despite the absence of valves, this tubular heart generates unidirectional blood flow. This fact poses the question how it works. Visual examination of the pulsating embryonic heart tube shows that its pumping action is characterized by traveling mechanical waves sweeping from its venous to its arterial end. These traveling waves were traditionally described as myocardial peristaltic waves. It has, therefore, been speculated that the tubular embryonic heart works as a technical peristaltic pump. Recent hemodynamic data from living embryos, however, have shown that the pumping function of the embryonic heart tube differs in several respects from that of a technical peristaltic pump. Some of these data suggest that embryonic heart tubes work as valveless "Liebau pumps." In the present study, a review is given on the evolution of the two above-mentioned theories of early cardiac pumping mechanics. We discuss pros and cons for both of these theories. We show that the tubular embryonic heart works neither as a technical peristaltic pump nor as a classic Liebau pump. The question regarding how the embryonic heart tube works still awaits an answer.
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http://dx.doi.org/10.1002/dvdy.22265DOI Listing
April 2010

Giant umbilical cord edema caused by retrograde micturition through an open patent urachus.

Pediatr Dev Pathol 2010 Sep-Oct;13(5):404-7. Epub 2010 Jan 19.

Department of Gastroenteropathology, University Medicine Göttingen, Robert-Koch-Straße 40, Göttingen, Germany.

A giant umbilical cord is a rare finding in mature newborns and originates from different developmental etiologies. We report on a case of a mature female newborn presenting a 50 × 8-cm giant umbilical cord without further malformations. Antenatal sonographic findings of a diffuse giant umbilical cord, elevated creatinine levels of 1.3 mg/dL in umbilical cord edema, gross and histopathological findings of allantoic remnants, and umbilical urinary discharge lead to the diagnosis of a patent urachus with retrograde micturition into the umbilical cord. Postnatal surgical repair was required. In antenatal sonography, cystic and diffuse changes should be considered in the differential diagnosis of a giant umbilical cord. In cases of diffuse enlargement, elevated umbilical creatinine can support the diagnosis of a patent urachus with open leakage into the Wharton's jelly. Appropriate surgical management is required.
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http://dx.doi.org/10.2350/09-10-0731-CR.1DOI Listing
February 2011

In vivo imaging of the cyclic changes in cross-sectional shape of the ventricular segment of pulsating embryonic chick hearts at stages 14 to 17: a contribution to the understanding of the ontogenesis of cardiac pumping function.

Dev Dyn 2009 Dec;238(12):3273-84

Department of Anatomy and Embryology, Georg-August-University of Göttingen, Göttingen, Germany.

The cardiac cycle-related deformations of tubular embryonic hearts were traditionally described as concentric narrowing and widening of a tube of circular cross-section. Using optical coherence tomography (OCT), we have recently shown that, during the cardiac cycle, only the myocardial tube undergoes concentric narrowing and widening while the endocardial tube undergoes eccentric narrowing and widening, having an elliptic cross-section at end-diastole and a slit-shaped cross-section at end-systole. Due to technical limitations, these analyses were confined to early stages of ventricular development (chick embryos, stages 10-13). Using a modified OCT-system, we now document, for the first time, the cyclic changes in cross-sectional shape of beating embryonic ventricles at stages 14 to 17. We show that during these stages (1) a large area of diminished cardiac jelly appears at the outer curvature of the ventricular region associated with formation of endocardial pouches; (2) the ventricular endocardial lumen acquires a bell-shaped cross-section at end-diastole and becomes compressed like a fireplace bellows during systole; (3) the contracting portions of the embryonic ventricles display stretching along its baso-apical axis at end-systole. The functional significance of our data is discussed with respect to early cardiac pumping function.
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http://dx.doi.org/10.1002/dvdy.22159DOI Listing
December 2009

Development of the proepicardium in Xenopus laevis.

Dev Dyn 2008 Oct;237(10):3088-96

Department of Anatomy and Embryology, Georg-August University of Göttingen, Germany.

The proepicardium (PE) is an embryonic progenitor cell population, which provides the epicardium, the majority of the cardiac interstitium, the coronary vasculature and possibly some cardiomyocytes. Recent studies have documented (1) the presence of bilaterally paired PE anlagen in several vertebrates, and (2) species-specific differences in the fate of the left and right PE anlagen. Here, we document PE development in Xenopus laevis (stages 37-46). The PE appears at stage 41 in the form of a cone-shaped accumulation of mesothelial cells covering the pericardial surface of the right horn of the sinus venosus. No such structure appears on the left sinus horn. At the end of stage 41, the tip of the PE establishes a firm contact with the developing ventricle. A secondary tissue bridge is established facilitating the transfer of PE cells to the heart. During stages 41-46, this tissue bridge is visible in vivo through the transparent body wall. Corresponding to the morphological data, the PE marker gene Tbx18 is expressed only on the right sinus horn suggesting a right-sided origin of the PE. Left-right lineage tracing has confirmed this idea. These results show that Xenopus PE development proceeds in a bilaterally asymmetric pattern as previously observed in chicks. We speculate that asymmetric PE development is controlled by signals from left-right signaling pathways and that the PE is an indicator for right-sidedness in Xenopus embryos. Xenopus might be a good model to uncover the role of left-right signaling pathways in the control of asymmetric PE development.
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http://dx.doi.org/10.1002/dvdy.21713DOI Listing
October 2008

The anatomy of cardiac looping: a step towards the understanding of the morphogenesis of several forms of congenital cardiac malformations.

Authors:
Jörg Männer

Clin Anat 2009 Jan;22(1):21-35

Department of Anatomy and Cell Biology, Georg-August-University of Göttingen, Kreuzbergring 36, Göttingen, Germany.

The early embryonic heart of vertebrates is a simple tubular pump. During the early phases of its development, the initially straight embryonic heart tube becomes transformed into a helically wound loop that is normally seen with a counterclockwise winding. This process is named cardiac looping. Such looping not only establishes the basic type of topological left-right asymmetry of the ventricular chambers but, additionally, is also said to bring the segments of the heart tube and the developing great vessels into an approximation of their definitive topographical relationships. Cardiac looping is, therefore, regarded as the key process in cardiac morphogenesis and pathologists have speculated since the beginning of the 20th century that several forms of congenital cardiac malformations (e.g., with mirror-imaged arrangement of the ventricular chambers) might result from disturbances in looping morphogenesis. In this article a review is given on (1) differences in the usage of the term cardiac looping; (2) our current knowledge of the dynamically changing anatomy of the looping embryonic heart; and (3) our current knowledge of the role of looping anomalies in the morphogenesis of congenital cardiac malformations.
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http://dx.doi.org/10.1002/ca.20652DOI Listing
January 2009

High-resolution in vivo imaging of the cross-sectional deformations of contracting embryonic heart loops using optical coherence tomography.

Dev Dyn 2008 Apr;237(4):953-61

Department of Anatomy and Embryology, Georg-August-University of Göttingen, Germany.

The embryonic heart tube consists of an outer myocardial tube, a middle layer of cardiac jelly, and an inner endocardial tube. It is said that tubular hearts pump the blood by peristaltoid contractions. The traditional concept of cardiac peristalsis sees the cyclic deformations of pulsating heart tubes as concentric narrowing and widening of tubes of circular cross-section. We have visualized the cross-sectional deformations of contracting embryonic hearts in chick embryos (HH-stages 9-17) using real-time high-resolution optical coherence tomography. Cardiac contractions are detected from HH-stage 10 onward. During the cardiac cycle, the myocardial tube undergoes concentric narrowing and widening while the endocardial tube undergoes eccentric narrowing and widening, having an elliptic cross-section at end-diastole and a slit-shaped cross-section at end-systole. The eccentric deformation of the endocardial tube is the consequence of an uneven distribution of the cardiac jelly. Our data show that the cyclic deformations of pulsating embryonic heart tubes run other than originally thought. There is evidence that heart tubes of elliptic cross-section might pump blood with a higher mechanical efficiency than those of circular-cross section. The uneven distribution of cardiac jelly seems to prefigure the future AV and cono-truncal endocardial cushions.
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http://dx.doi.org/10.1002/dvdy.21483DOI Listing
April 2008

Epicardium-derived progenitor cells require beta-catenin for coronary artery formation.

Proc Natl Acad Sci U S A 2007 Nov 7;104(46):18109-14. Epub 2007 Nov 7.

Development and Aging Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

We have previously identified several members of the Wnt/beta-catenin pathway that are differentially expressed in a mouse model with deficient coronary vessel formation. Systemic ablation of beta-catenin expression affects mouse development at gastrulation with failure of both mesoderm development and axis formation. To circumvent this early embryonic lethality and study the specific role of beta-catenin in coronary arteriogenesis, we have generated conditional beta-catenin-deletion mutant animals in the proepicardium by interbreeding with a Cre-expressing mouse that targets coronary progenitor cells in the proepicardium and its derivatives. Ablation of beta-catenin in the proepicardium results in lethality between embryonic day 15 and birth. Mutant mice display impaired coronary artery formation, whereas the venous system and microvasculature are normal. Analysis of proepicardial beta-catenin mutant cells in the context of an epicardial tracer mouse reveals that the formation of the proepicardium, the migration of proepicardial cells to the heart, and the formation of the primitive epicardium are unaffected. However, subsequent processes of epicardial development are dramatically impaired in epicardial-beta-catenin mutant mice, including failed expansion of the subepicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived mesenchymal cells into coronary smooth muscle cells. Our data demonstrate a functional role of the epicardial beta-catenin pathway in coronary arteriogenesis.
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http://dx.doi.org/10.1073/pnas.0702415104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084304PMC
November 2007

Construction and establishment of a new environmental chamber to study real-time cardiac development.

Microsc Microanal 2007 Jun;13(3):204-10

Department of Pediatric Cardiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Heart development, especially the critical phase of cardiac looping, is a complex and intricate process that has not yet been visualized "live" over long periods of time. We have constructed and established a new environmental incubator chamber that provides stable conditions for embryonic development with regard to temperature, humidity, and oxygen levels. We have integrated a video microscope in the chamber to visualize the developing heart in real time and present the first "live" recordings of a chick embryo in shell-less culture acquired over a period of 2 days. The time-lapse images we show depict a significant time window that covers the most critical and typical morphogenetic events during normal cardiac looping. Our system is of interest to researchers in the field of embryogenesis, as it can be adapted to a variety of animal models for organogenesis studies including heart and limb development.
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http://dx.doi.org/10.1017/S1431927607070390DOI Listing
June 2007

Early morphogenesis of the sinuatrial region of the chick heart: a contribution to the understanding of the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.

Anat Rec (Hoboken) 2007 Feb;290(2):168-80

Department of Anatomy and Embryology, Georg August University, Göttingen, Germany.

The morphogenesis of the sinuatrial region of embryonic hearts is still not well understood. Current matters of dispute are the topogenesis of the future pulmonary vein orifice and the topogenesis of the primary atrial septum. We analyzed the development of the sinuatrial region in chick embryos ranging from Hamburger and Hamilton (HH) stage 14 to 25. Our study disclosed three features of sinuatrial development. First, the primitive atrium of the HH stage 16 chick embryo heart has a separate inflow component. This inflow component takes up the mouth of the confluence of the systemic veins (sinus venosus) as well as the future mouth of the common pulmonary vein (pulmonary pit). The left portion of the atrial inflow component becomes incorporated into the left atrium and its right portion becomes incorporated into the right atrium. Rightward growth of the sinuatrial fold separates the sinus venosus from the left atrium. Second, the pulmonary pit originally forms as a bilaterally paired structure. Its left and right portions are connected to the left and right portions of the atrial inflow component, respectively. Normally, only the left portion of the pulmonary pit deepens to form the common pulmonary vein orifice, whereas the right portion disappears. Third, the primary atrial septum of the chick heart is not formed at the original midline of the embryonic heart, but is formed to the left of the original midline. This finding is in accord with molecular data suggesting that the primary atrial septum derives from the left heart-forming field. Our findings shed new light on the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.
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http://dx.doi.org/10.1002/ar.20418DOI Listing
February 2007

The proepicardium delivers hemangioblasts but not lymphangioblasts to the developing heart.

Dev Biol 2007 May 28;305(2):451-9. Epub 2007 Feb 28.

Children's Hospital, Pediatrics I, University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.

The mass of the myocardium and endocardium of the vertebrate heart derive from the heart-forming fields of the lateral plate mesoderm. Further components of the mature heart such as the epicardium, cardiac interstitium and coronary blood vessels originate from a primarily extracardiac progenitor cell population: the proepicardium (PE). The coronary blood vessels are accompanied by lymph vessels, suggesting a common origin of the two vessel types. However, the origin of cardiac lymphatics has not been studied yet. We have grafted PE of HH-stage 17 (day 3) quail embryos hetero- and homotopically into chick embryos, which were re-incubated until day 15. Double staining with the quail endothelial cell (EC) marker QH1 and the lymphendothelial marker Prox1 shows that the PE of avian embryos delivers hemangioblasts but not lymphangioblasts. We have never observed quail ECs in lymphatics of the chick host. However, one exception was a large lymphatic trunk at the base of the chick heart, indicating a lympho-venous anastomosis and a 'homing' mechanism of venous ECs into the lymphatic trunk. Cardiac lymphatics grow from the base toward the apex of the heart. In murine embryos, we observed a basal to apical gradient of scattered Lyve-1+/CD31+/CD45+ cells in the subepicardium at embryonic day 12.5, indicating a contribution of immigrating lymphangioblasts to the cardiac lymphatic system. Our studies show that coronary blood and lymph vessels are derived from different sources, but grow in close association with each other.
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http://dx.doi.org/10.1016/j.ydbio.2007.02.026DOI Listing
May 2007

Morphological and molecular left-right asymmetries in the development of the proepicardium: a comparative analysis on mouse and chick embryos.

Dev Dyn 2007 Mar;236(3):684-95

Department of Anatomy and Embryology, Georg-August University of Göttingen, Germany.

The proepicardium (PE) is an embryonic progenitor cell population that delivers the epicardium, the majority of the cardiac interstitium, and the coronary vasculature. In the present study, we compared PE development in mouse and chick embryos. In the mouse, a left and a right PE anlage appear simultaneously, which subsequently merge at the embryonic midline to form a single PE. In chick embryos, the right PE anlage appears earlier than the left and only the right anlage acquires the full PE-phenotype. The left anlage remains in a rudimentary state. The expression patterns of PE marker genes (Tbx18, Wt1) correspond to the morphological data, being bilateral in the mouse and unilateral in the chick. Bmp4, which is unilaterally expressed in the right PE of chick embryos, is symmetrically expressed in the sinus venosus wall cranial to the PE in mouse embryos. Asymmetric development of the chicken PE might reflect side-specific differences in topographical relationships to tissues with PE-inducing or repressing activity or might result from the PE-repressing activity of the right PE, which grows earlier. To test these hypotheses, we analyzed PE development in chick embryos, firstly, subsequent to experimentally induced inversion of PE topographical relationships to neighbouring tissues; secondly, in organ cultures; and, thirdly, subsequent to induction of cardia bifida. In all three experiments, only the right PE develops the full PE phenotype. Our results suggest that PE development might be controlled by the L-R pathway in the chick but not in the mouse embryo.
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http://dx.doi.org/10.1002/dvdy.21065DOI Listing
March 2007

The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart.

Cardiovasc Res 2006 Nov 29;72(2):198-209. Epub 2006 Jun 29.

Department of Biochemistry and Molecular Biology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.

The heart is one of the first organs to function in the developing embryo. Vertebrate heart development can be subdivided into different phases, e.g. specification of myo- and endocardial progenitor cells during the establishment of heart-forming fields within the anterior lateral plate mesoderm, formation of the linear heart tube by merging of the paired heart-forming fields in front of the foregut, looping of the heart tube and transformation of the tubular embryonic heart into the four-chambered heart. The molecular mechanisms underlying these processes are phylogenetically remarkably conserved and involve the activation of specific transcriptional programs by different extracellular growth factors. In this review, we will focus on the functions of the Wnt family of growth factors in normal cardiac development and in tissue remodelling in the mature heart under pathological conditions.
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http://dx.doi.org/10.1016/j.cardiores.2006.06.025DOI Listing
November 2006