FIH-1, a Novel Interactor of Mindbomb, Functions as an Essential Anti-Angiogenic Factor during Zebrafish Vascular Development

<div><p>Objective</p><p>It has been shown that Mindbomb (Mib), an E3 Ubiquitin ligase, is an essential modulator of Notch signaling during development. However, its effects on vascular development remain largely unknown.</p><p>Approaches and Results</p><p>We identified a number of novel proteins that physically interact with Mib, including the Factor Inhibiting Hypoxia Inducible Factor 1 (FIH-1, also known as HIF1AN) from a yeast two hybrid screen, as previously reported. In cultured cells, FIH-1 colocalizes with Mib1, corroborating their potential interaction. In zebrafish embryos, FIH-1 appears to modulate VEGF-A signaling activity; depletion of <i>fih-1</i> induces ectopic expression of <i>vascular endothelial growth factor–a</i> (<i>vegfa</i>) and leads to exuberant ectopic sprouts from intersegmental vessels (ISVs). Conversely, over-expression of <i>fih-1</i> substantially attenuates the formation of ISVs, which can be rescued by concurrent over-expression of <i>vegfa</i>, indicating that FIH-1/HIF1AN may fine tune VEGF-A signaling.</p><p>Conclusions</p><p>Taken together, our data suggest that FIH-1 interacts with Mib E3 Ubiquitin ligase and modulates vascular development by attenuating VEGF-A signaling activity.</p>