Abstract
Cardiac transcription factors orchestrate the complex cellular and molecular events required to produce a functioning heart. Misregulation of the cardiac transcription program leads to embryonic developmental defects and is associated with human congenital heart diseases. Recent studies have expanded our understanding of the regulation of cardiac gene expression at an additional layer, involving the coordination of epigenetic and transcriptional regulators. In this review, we highlight and discuss discoveries made possible by the genetic and embryological tools available in the zebrafish model organism, with a focus on the novel functions of cardiac transcription factors and epigenetic and transcriptional regulatory proteins during cardiogenesis.
Highlights
Cardiac morphogenesis and the maintenance of cardiac physiology require dynamic and carefully coordinated transcription programs
A multitude of novel findings in zebrafish have helped to identify the critical mechanisms by which cardiac transcription factors, chromatin remodeling proteins, and general transcriptional regulators shape the developing heart and demonstrate the power of using zebrafish as a model to increase our knowledge about cardiogenesis
A deeper understanding of the steps of cardiogenesis is critical for deciphering the molecular mechanisms underlying congenital heart defects and developing novel regenerative therapies for cardiovascular disease
Summary
Cardiac morphogenesis and the maintenance of cardiac physiology require dynamic and carefully coordinated transcription programs. Studies in pluripotent stem cells and multiple model organisms have delineated critical signaling events involving Bmp, Fgf, Wnt, and Notch that induce the expression of a set of cardiogenic transcription factors to drive cardiac specification and differentiation (for review see [1,2,3]). The activation of an evolutionarily conserved cardiac transcription program including GATA factors, Hand, T-box proteins, and Nkx2.5 specifies cardiac progenitors within the anterior lateral plate mesoderm (ALPM), which subsequently migrate toward the midline of the embryo, turn on expression of cardiac sarcomere proteins, and fuse to form a beating heart tube. Dis. 2016, 3, 14 is downregulated in zebrafish gata5/6 double morphants Both excessive and reduced tmem88a expression disrupt nkx2.5 expression in the ALPM, consistent with the biphasic function of Wnt signaling in cardiac development and highlighting a dosage-sensitive requirement for Tmem88a [16]. Knockdown of Tmem88a during directed cardiac differentiation of human ES cells increases Wnt/β-catenin signaling and results in a reduced number of cardiac progenitor cells [17], pointing to a critical role of Tmem88a in mediating crosstalk between GATA factors and the Wnt signaling pathway
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