MicroRNAs in cardiac development

Abstract

The transcriptional regulation of cardiovascular development requires precise spatiotemporal control of gene expression, and heterozygous mutations of transcription factors have frequently been implicated in human cardiovascular malformations. A novel mechanism involving post-transcriptional regulation by small, noncoding microRNAs (miRNAs) has emerged as a central regulator of many cardiogenic processes. We are beginning to understand the functions that miRNAs play during essential biologic processes, such as cell proliferation, differentiation, apoptosis, stress response, and tumorigenesis. The identification of miRNAs expressed in specific cardiac and vascular cell types has led to the discovery of important regulatory roles for these small RNAs during cardiomyocyte differentiation, cell cycle, conduction, and vessel formation. Here, we overview the recent findings on miRNA regulation in cardiovascular development. Further analysis of miRNA function during cardiovascular development will allow us to determine the potential for novel miRNA-based therapeutic strategies.

Fig. 1

Schematic representation of miRNA biogenesis and function. Transcription of miRNA genes is typically mediated by RNA polymerase II (pol II) and can be controlled by various transcription factors (TF). The initial transcripts, termed “primiRNAs,” can range from a few hundred nucleotides to several kilobases long. The primiRNA has a characteristic stem-loop structure that can be recognized and cleaved by the RNase III endonuclease Drosha, along with its partner DGCR8 (DiGeorge syndrome critical region 8 gene; also known as Pasha). The cleavage product, an approximately 70-nt stem-loop pre-miRNA, is exported from the nucleus by Exportin 5. In the cytoplasm, another RNase III enzyme, Dicer, further cleaves the pre-miRNA into a double-stranded mature miRNA (approximately 21 nt), which is incorporated into the RISC, thus allowing preferential strand separation of the mature miRNA to repress mRNA translation or destabilize mRNA transcripts through cleavage or deadenylation (adapted from Zhao and Srivastava [57])

Fig. 2

Summary of miR-1 and miR-133 genomic organization, regulation, and expression during mouse cardiogenesis. a Chromosomal locations of mouse miR-1 and miR-133a. The miR-1/133a clusters are transcribed as bicistronic transcripts. b LacZ directed by an upstream enhancer of the miR-1-2/miR-133a-2 and miR-1-1 miR-133a-1 clusters, respectively, shows expression in the heart (ht) and somites (arrowhead) at mouse embryonic day 11.5. c Cardiac expression of miR-1 and miR-133 is regulated by SRF. Targets of miR-1 and miR-133 in cardiac muscle are shown

Fig. 3

Model of miR-1/miR-133 effects during embryonic stem-cell differentiation. miR-1 and miR-133 promote differentiation of mesoderm and inhibit endoderm and ectoderm differentiation at specific stages as indicated and have opposing effects in later steps of muscle differentiation. miR-1 inhibition of Dll-1 translation, along with yet unknown targets, likely contribute to the observed effects of miR-1 (from Ivey et al. [20])

Fig. 4

miR-143 and miR-145 are transcriptionally regulated by SRF and repress multiple factors that normally promote the synthetic smooth-muscle phenotype (lavender). These include Klf4, which interacts with SRF and also represses Myocd. miR-145 has a positive effect on Myocd activity to concurrently promote the contractile smooth-muscle phenotype (peach), thereby also reinforcing miR-145 and miR-143 expression (from Cordes et al. [12])