Foxf1-mediated co-regulation of miR-495 and let-7c modulates epicardial cell migration and myocardial specification

The heart is the first functional organ to develop in the vertebrate embryos. In mice, the primitive tubular heart begins beating at embryonic day (E) 8.0-E.8.5 and undergoes rightward looping to form the atrial and ventricular chambers. The proepicardium, a transient cell cluster at the sinus venous-lateral plate mesenchyme junction migrates onto the heart and gives rise to the embryonic epicardium, a squamous epithelium that plays a key role in cardiac development. Despite advances in understanding epicardial lineage contributions, the molecular mechanisms governing these processes remain poorly understood.

To characterize the transcriptional and post-transcriptional regulation of epicardial development, we performed RNA sequencing at two critical timepoints, proepicardium formation and embryonic epicardium establishment. We analysed differentially expressed coding and non-coding RNAs, focusing on microRNAs and their potential regulatory interactions.

We identified a complex network involving differentially expressed mRNAs, microRNAs and lncRNAs between proepicardium and embryonic epicardium. Notably, with miR-495 and let-7c emerged as key regulators of epicardial cell migration, an essential process for proper epicardium formation and epicardial-derived cell migration. Our findings also reveal that these microRNAs not only regulate target gene expression but also modulate other microRNAs, suggesting a novel regulatory mechanism in epicardial development. Additionally, Foxf1 inhibition modulates let-7c, promoting the expression of key cardiogenic lineage markers in epicardial cells.

Our study highlights the role of Foxf1 in regulating miR-495 and let-7c, which in turn modulate epicardial cell migration and myocardial specification. These finding provide new insights into the intricate interplay between transcription factors and microRNAs in governing cardiogenesis.