Review ArticleGenetic insights into normal and abnormal heart development☆,☆☆
Section snippets
Heart development: from lineages to chambers
In higher vertebrates, heart formation is a complex process (Fig. 1) that starts at early stages of embryogenesis, prior to the end of gastrulation, with commitment of anterior lateral plate mesoderm cells to the cardiogenic lineage and their migration and organization into the cardiac crescent. Commitment to a cardiac fate is the result of inductive signals from the underlying endoderm, which include bone morphogenetic proteins (BMPs), basic fibroblast growth factors, and the Wnt proteins. The
Cardiac transcription: a multipartner affair
The complex morphologic events and tissue remodeling that take place during heart formation are accompanied by equally complex changes of gene expression that produce dynamically regulated chamber as well as left–right specific patterns. Despite important efforts devoted to the study of chamber-specific gene expression and the identification of several cardiac TFs involved in heart formation (Fig. 1 and Table 1), the molecular mechanisms underlying spatiotemporal regulation of transcription
CHD: an enigma of variable expressivity and multiple genes
Septal and valvular defects are the most frequently occurring CHDs [45]. They range in severity from relatively minor, even subclinical defects like patent foramen oval (PFO), to complex malformations like tetralogy of Fallot or tricuspid atresia that can be life threatening. Although minor subclinical defects do not interfere significantly with heart function initially, with time, they can impair exercise tolerance, such as atrial septal defects (ASDs), and in general, they represent risk
Conclusion and future directions
Cardiac development is a complex and highly regulated interplay of genes and cell–cell interactions. The past decade has witnessed spectacular progress in elucidating the molecular mechanisms of heart formation. In particular, several genes essential for heart development have been identified. Genetic analysis using classical human genetic approaches, as well as the direct sequencing of candidate genes—which are essential for normal heart formation—in families with affected members, has started
Acknowledgment
I am indebted to past and present members of my laboratory for their invaluable contributions over the years. Special thanks to L. Laroche for excellent secretarial support and P. Paradis for editorial assistance. M.N. holds the Canada Research Chair in Cardiovascular Growth and Differentiation.
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2022, Biochemical PharmacologyCitation Excerpt :As an example, Tbx2 and Tbx3 are selectively expressed in the cardiac conduction tissue where they repress the transcription of atrial and ventricular muscle cell-specific genes by interacting with and inhibiting the protranscriptional activity of Nkx2-5 [73,74]. In accordance with this critical role during cardiogenesis, rare mutations in the genes encoding these TFs are usually associated with congenital cardiac defects [11,65–67,75]. As mentioned above, recent evidence, especially that obtained in GWAS performed in large cohorts of control individuals and cases in the context of AF [76], suggested an association of TFs with the control of cardiac electrical activity and susceptibility to arrhythmias [13,14].
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The work carried out in the author's laboratory is supported by the Canadian Institutes of Health Research.
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This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, San Diego, CA, February 2007.