Genetic regulation of cardiogenesis and congenital heart disease

Gladstone Institute of Cardiovascular Disease, Department of Pediatrics, University of California, San Francisco, California 94158, USA.
Annual Review of Pathology Mechanisms of Disease (Impact Factor: 18.75). 02/2006; 1(1):199-213. DOI: 10.1146/annurev.pathol.1.110304.100039
Source: PubMed


Developmental heart disorders are the most common of all human birth defects and occur in nearly one percent of the population. Survivors of congenital heart malformations are an increasing population, and it is becoming clear that genetic mutations that cause developmental anomalies may result in cardiac dysfunction later in life. This review highlights the progress in understanding the underlying molecular basis for cardiac formation and how disruption of the intricate steps of cardiogenesis can lead to congenital heart defects. The lessons learned from examining the early steps of heart formation are essential for informing the prevention of malformations and their long-term consequences, as well as for approaches to guide stem cells into cardiac lineages.

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    • "Heart formation is a complex morphogenetic process involving specification, differentiation, and migration of cardiac progenitor cells. Defects in this program are responsible for the high rate of congenital cardiac abnormalities in humans underscoring the importance of understanding the molecular mechanisms regulating cardiogenesis (Bruneau, 2008; Srivastava, 2006a). Using different model systems, including Drosophila, Xenopus, zebrafish , chick, and mouse, substantial progress has been made to unveil the principal mechanisms and the key molecular players driving heart development. "
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    ABSTRACT: Morphogenesis of the heart requires tight control of cardiac progenitor cell specification, expansion, and differentiation. Retinoic acid (RA) signaling restricts expansion of the second heart field (SHF), serving as an important morphogen in heart development. Here, we identify the LIM domain protein Ajuba as a crucial regulator of the SHF progenitor cell specification and expansion. Ajuba-deficient zebrafish embryos show an increased pool of Isl1(+) cardiac progenitors and, subsequently, dramatically increased numbers of cardiomyocytes at the arterial and venous poles. Furthermore, we show that Ajuba binds Isl1, represses its transcriptional activity, and is also required for autorepression of Isl1 expression in an RA-dependent manner. Lack of Ajuba abrogates the RA-dependent restriction of Isl1(+) cardiac cells. We conclude that Ajuba plays a central role in regulating the SHF during heart development by linking RA signaling to the function of Isl1, a key transcription factor in cardiac progenitor cells.
    Developmental Cell 07/2012; 23(1):58-70. DOI:10.1016/j.devcel.2012.06.005 · 9.71 Impact Factor
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    • "Genetic ablation of many of these components in mice leads to developmental pathologies that are similar to those that form in humans with congenital heart defects (Srivastava, 2006). Extracellular matrix (ECM)-regulated adhesion and signaling pathways are also important for normal heart development . "
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    ABSTRACT: Morphogenesis of the heart is regulated by various cues, including growth factors and extracellular matrix (ECM) proteins. The mechanisms by which cardiac cells properly integrate these cues to regulate growth, differentiation, and migration remain poorly understood. Here we have used genetic strategies in mice to identify αvβ8 integrin and its cytoskeletal adaptor protein, Band 4.1B, as essential regulators of cardiac morphogenesis. We demonstrate that approximately 60% of mouse embryos genetically null for β8 integrin and Band 4.1B display cardiovascular phenotypes and die by E11.5. This premature death is due, in part, to defective development of the cardiac outflow tract (OFT), with reduced expression of smooth muscle α-actin (SMAα-actin) in OFT cells derived from the cardiac neural crest. These data are the first to identify cell adhesion and signaling pathways regulated by αvβ8 integrin and Band 4.1B as essential for normal formation and function of the heart during embryogenesis.
    Developmental Dynamics 01/2011; 240(1):271-7. DOI:10.1002/dvdy.22513 · 2.38 Impact Factor
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    • "Among all birth defects, cardiac anomalies are the most prevalent. The causes of birth defects can be divided between those due to genetic factors, as caused by mutations in specific genes or chromosomal abnormalities [1], or those induced by environmental causes, as by drugs, environmental chemicals, or by abnormal concentrations of natural metabolites [2] [3] [4] [5]. This article will provide an overview of new cell and molecular data from studies in vertebrate models on underlying mechanisms associated with induction of congenital heart defects by environmental factors during a critical early window of development and new evidence on cardiac protection by folate and myo-inositol supplementation. "
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    ABSTRACT: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors: alcohol, the drug lithium, and the metabolite homocysteine, impacting the Wnt/β-catenin pathway during cardiac development and folate protection. Animal and epidemiological studies have shown that folate protects the embryo from birth defects. New animal studies demonstrate that folate prevents cardiovascular defects induced by the drug lithium, homocysteine, or alcohol, but protection occurs at a higher concentration than currently used in vitamin supplements. The data indicate that folate in combination with myo-inositol may further reduce the risk of birth defects. Discussion is presented of the cell specification stages that are impacted resulting in cardiac defects, how Wnt/β-catenin signaling is involved, and how folate and myo-inositol additively may protect embryonic pathways. The possible epigenetic role of folate in Wnt/β-catenin signaling is described. This review will enable better counseling of women by defining, during early pregnancy, a susceptible window of embryonic exposure leading to a high risk of cardiac defects, and provides a therapeutic means and the necessary timing for prevention of environmentally induced birth defects.
    Current opinion in pediatrics 10/2010; 22(5):561-6. DOI:10.1097/MOP.0b013e32833e2723 · 2.53 Impact Factor
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