A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish

Abstract

Members of the Slit family of secreted ligands interact with Roundabout (Robo) receptors to provide guidance cues for many cell types. For example, Slit/Robo signaling elicits repulsion of axons during neural development, whereas in endothelial cells this pathway inhibits or promotes angiogenesis depending on the cellular context. Here, we show that miR-218 is intronically encoded in slit2 and slit3 and that it suppresses Robo1 and Robo2 expression. Our data indicate that miR-218 and multiple Slit/Robo signaling components are required for heart tube formation in zebrafish and that this network modulates the previously unappreciated function of Vegf signaling in this process. These findings suggest a new paradigm for microRNA-based control of ligand-receptor interactions and provide evidence for a novel signaling pathway regulating vertebrate heart tube assembly.

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

“…The most interesting candidates appeared to be miR-34 and miR-30a, which regulate the expression of genes that are involved in cardiac morphogenesis, cell proliferation, and contraction. One of the affected target genes that was identified, robo1 (roundabout guidance receptor 1), is involved in tube formation of the developing zebrafish heart (26). Robo1 is also a confirmed target gene of the aforementioned miR-218 in several organs, including the heart (26,61,62), and a putative target of miR-30a.…”

“…One of the affected target genes that was identified, robo1 (roundabout guidance receptor 1), is involved in tube formation of the developing zebrafish heart (26). Robo1 is also a confirmed target gene of the aforementioned miR-218 in several organs, including the heart (26,61,62), and a putative target of miR-30a. Thus, two different miRs that are dysregulated upon tbx5-depletion in zebrafish both negatively affect the expression of robo1, a gene that is essential for proper heart development.…”

The admiR-able advances in cardiovascular biology through the zebrafish model system

“…Fish et al [102] demonstrated that the Slit/ miRNA-218/robo signaling pathway regulates migration of heart precursors in the midline, in part modulating Vegf signaling in the endocardium. The authors observed that downregulation of miRNA-218 causes a delayed heart field migration that results in pericardial edema and abnormal heart looping.…”

Drosophila Model of Congenital Heart Diseases

“…Both, Slit and Robo are expressed during mouse heart development and expression of Slit3 and Robo2 depend on Tbx20 and Nkx2-5, respectively (Medioni et al, 2010). Functional analysis in zebrafish done by Fish et al (2011) indicates a role for Slit/Robo signaling during zebrafish heart development. Slit/robo mutant fish hearts show a number of developmental defects, indicating a conserved requirement for this pathway during vertebrate cardiogenesis and thus a role in CHD.…”