Fig. 7.

Model of a Slit/miR-218/Robo axis that regulates Vegf signaling and endocardial migration. Slit2 inhibits the migration of the endocardium to the midline through a combination of negative regulation of the Vegf signaling pathway and Slit/Robo-mediated repulsion signals. During midline migration, the endocardium is likely to sense Slit2 secreted by the floor plate; however, autocrine signaling may also play a role in endocardial migration. The identity of the Slit2 receptor(s) that mediates the negative regulation of Vegf signaling is unclear as this effect appears to be at least partly Robo4 independent. The Slit2/3-encoded microRNA miR-218 targets Robo1 (and Robo2 and Srgap2, not shown) for repression. Robo1 positively regulates endocardial migration, perhaps by promoting the auto-phosphorylation of Vegfr2. However, increased Robo1 expression in miR-218 morphants may mediate Slit/Robo-mediated repulsion, suggesting that miR-218 might titrate the levels of Robo1 to facilitate heart field migration.