Can recent insights into cardiac development improve our understanding of congenitally malformed hearts?

Horsthuis, Thomas; Christoffels, Vincent M.; Anderson, Robert H.; Moorman, Antoon F.M.

doi:10.1002/ca.20723

Cited by 22 publications

(11 citation statements)

References 78 publications

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“…In the past years molecular mechanisms underlying cardiac morphogenesis were studied in vivo by the generation of gene-targeted animal models [34]. The heart is composed of early progenitor cells from at least two sources located in bilateral cardiogenic fields [13].…”

Section: Cardiac Developmentmentioning

confidence: 99%

Molecular genetics of congenital atrial septal defects

et al. 2009

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Congenital heart defects (CHD) are the most common developmental errors in humans, affecting 8 out of 1,000 newborns. Clinical diagnosis and treatment of CHD has dramatically improved in the last decades. Hence, the majority of CHD patients are now reaching reproductive age. While the risk of familial recurrence has been evaluated in various population studies, little is known about the genetic pathogenesis of CHD. In recent years significant progress has been made in uncovering genetic processes during cardiac development. Data from human genetic studies in CHD patients indicate that the genetic aetiology was presumably underestimated in the past. Inherited mutations in genes encoding cardiac transcription factors and sarcomeric proteins were found as an underlying cause for familial recurrence of non-syndromic CHD in humans, in particular cardiac septal defects. Notably, the cardiac phenotypes most frequently seen in mutation carriers are ostium secundum atrial septal defects (ASDII). This review outlines experimental approaches employed for the detection of CHD-related genes in humans and summarizes recent findings in molecular genetics of congenital cardiac septal defects with an emphasis on ASDII.

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Section: Cardiac Developmentmentioning

confidence: 99%

Molecular genetics of congenital atrial septal defects

et al. 2009

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“…The second heart field (SHF) is a progenitor population of splanchnic and pharyngeal mesoderm that is located dorsal to the pericardial cavity. SHF cells are added progressively to both ends of the heart tube (Buckingham et al, 2005; Horsthuis et al, 2009), in mouse during the E8.0–10.5 period, fully constituting the right ventricle and outflow tract (OFT) and contributing to portions of both atrial chambers at the inflow region of the heart.…”

Section: Introductionmentioning

confidence: 99%

Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFβ-Mediated Outflow Tract Septation

Pashmforoush

Sucov

2010

Developmental Cell

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SUMMARY In many experimental models and clinical examples, defects in the differentiation of the second heart field (SHF) and heart outflow tract septation defects are combined, although the mechanistic basis for this relationship has been unclear. We found that as the initial SHF population incorporates into the outflow tract, it is replenished from the surrounding progenitor territory. In retinoic acid (RA) receptor mutant mice, this latter process fails, and the outflow tract is shortened and misaligned as a result. As an additional consequence, the outflow tract is misspecified along its proximal-distal axis, which results in ectopic expression of TGFβ2 and ectopic mesenchymal transformation of the endocardium. Reduction of TGFβ2 gene dosage in the RA receptor deficient background restores septation but does not rescue alignment defects, indicating that excess TGFβ causes septation defects. This may be a common pathogenic pathway when second heart field and septation defects are coupled.

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“…In humans, cardiac defects are the most common serious anomalies among live births with an estimated frequency of 0.6% 1. Numerous mouse models of congenital heart disease have been generated and characterized, adding greater insight into the molecular and cellular origins of these defects 2. In addition, current research in the area of targeted gene deletions holds great promise to further elucidate mechanisms of cardiac development.…”

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confidence: 99%

Rapid 3D Phenotyping of Cardiovascular Development in Mouse Embryos by Micro-CT With Iodine Staining

Degenhardt

Wright

Horng

et al. 2010

Circ: Cardiovascular Imaging

235

290

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Background-Microcomputed tomography (micro-CT) has been used extensively in research to generate high-resolution 3D images of calcified tissues in small animals nondestructively. It has been especially useful for the characterization of skeletal mutations but limited in its utility for the analysis of soft tissue such as the cardiovascular system. Visualization of the cardiovascular system has been largely restricted to structures that can be filled with radiopaque intravascular contrast agents in adult animals. Recent ex vivo studies using osmium tetroxide, iodinated contrast agents, inorganic iodine, and phosphotungstic acid have demonstrated the ability to stain soft tissues differentially, allowing for high intertissue contrast in micro-CT images. In the present study, we demonstrate the application of this technology for visualization of cardiovascular structures in developing mouse embryos using Lugol solution (aqueous potassium iodide plus iodine). Methods and Results-We show the optimization of this method to obtain ex vivo micro-CT images of embryonic and neonatal mice with excellent soft-tissue contrast. We demonstrate the utility of this method to visualize key structures during cardiovascular development at various stages of embryogenesis. Our method benefits from the ease of sample preparation, low toxicity, and low cost. Furthermore, we show how multiple cardiac defects can be demonstrated by micro-CT in a single specimen with a known genetic lesion. Indeed, a previously undescribed cardiac venous abnormality is revealed in a PlexinD1 mutant mouse. Conclusions-Micro-CT of iodine-stained tissue is a valuable technique for the characterization of cardiovascular development and defects in mouse models of congenital heart disease. (Circ Cardiovasc Imaging. 2010;3:314-322.)Key Words: micro-CT Ⅲ iodine Ⅲ mouse Ⅲ development Ⅲ PlexinD1 Ⅲ congenital heart disease T he ability to genetically manipulate the mouse has resulted in a powerful model system for the investigation of many disease processes. In particular, genetic studies in the mouse have enhanced our understanding of embryonic development, and by extension, of congenital defects. In humans, cardiac defects are the most common serious anomalies among live births with an estimated frequency of 0.6%. 1 Numerous mouse models of congenital heart disease have been generated and characterized, adding greater insight into the molecular and cellular origins of these defects. 2 In addition, current research in the area of targeted gene deletions holds great promise to further elucidate mechanisms of cardiac development. Editorial see p 228 Clinical Perspective on p 322Although structurally similar to the human, the significantly reduced size of the murine cardiovascular system presents a number of technical challenges when attempting to stage anatomic features such as vascular structures. Identification and characterization of the phenotype of cardiovascular defects in mice traditionally has relied on histological analysis of sectioned specimens. Histology,...

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Can recent insights into cardiac development improve our understanding of congenitally malformed hearts?

Cited by 22 publications

References 78 publications

Molecular genetics of congenital atrial septal defects

Molecular genetics of congenital atrial septal defects

Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFβ-Mediated Outflow Tract Septation

Rapid 3D Phenotyping of Cardiovascular Development in Mouse Embryos by Micro-CT With Iodine Staining

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