Abstract
Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo. The precardiac mesoderm subsequently fused at the embryonic midline constituting an embryonic linear heart tube. As development progress, the embryonic heart displays the first sign of left-right asymmetric morphology by the invariably rightward looping of the initial heart tube and prospective embryonic ventricular and atrial chambers emerged. As cardiac development progresses, the atrial and ventricular chambers enlarged and distinct left and right compartments emerge as consequence of the formation of the interatrial and interventricular septa, respectively. The last steps of cardiac morphogenesis are represented by the completion of atrial and ventricular septation, resulting in the configuration of a double circuitry with distinct systemic and pulmonary chambers, each of them with distinct inlets and outlets connections. Over the last decade, our understanding of the contribution of multiple growth factor signaling cascades such as Tgf-beta, Bmp and Wnt signaling as well as of transcriptional regulators to cardiac morphogenesis have greatly enlarged. Recently, a novel layer of complexity has emerged with the discovery of non-coding RNAs, particularly microRNAs and lncRNAs. Herein, we provide a state-of-the-art review of the contribution of non-coding RNAs during cardiac development. microRNAs and lncRNAs have been reported to functional modulate all stages of cardiac morphogenesis, spanning from lateral plate mesoderm formation to outflow tract septation, by modulating major growth factor signaling pathways as well as those transcriptional regulators involved in cardiac development.
Highlights
Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo
Whereas transcriptional regulation constitutes a major step governing and defining the molecular mechanisms that direct cardiac morphogenesis and cardiovascular cell differentiation, a novel layer of gene regulation is emerging with the discovery of noncoding RNAs
Regulation of Smad4 by microRNAs have been documented in distinct cardiovascular settings [339,340], such as regulation by miR-34 and miR-122 in cardiac fibrosis [340], by miR-146a-5p in exosomes of human cardiacresident mesenchymal progenitor cells (CPC) [341], by miR-26a in hypertension-induced myocardial fibrosis [342], yet the only evidence on the regulatory role of microRNAs in cardiovascular development has been established by Dong et al [343]
Summary
Specification, differentiation and development of cardiac progenitors are subjected to intense paracrine regulation mediated by different growth factors, bone morphogenetic proteins (Bmps), fibroblastic growth factors (Fgfs), transforming growth factors (Tfgs) and Wnt signaling [1–3]. These growth factor signals contribute to additional cardiac morphogenetic processes, such as proepicardial/epicardial development [4–9], endocardial cushion formation [10–16] and outflow tract remodeling [14,17–19]. Several other signaling pathways are required for discrete cardiovascular morphogenetic processes, such as Hippo pathway that is fundamental for cardiomyocyte proliferation and organ size determination [20–22], and Notch and neuregulin signaling. Evidence of the functional role of non-coding RNAs impacting on these signaling pathways has been recently reported as detailed in the following subheadings
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