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

Abstract

ObjectiveIt 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.Approaches and ResultsWe 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 fih-1 induces ectopic expression of vascular endothelial growth factor–a (vegfa) and leads to exuberant ectopic sprouts from intersegmental vessels (ISVs). Conversely, over-expression of fih-1 substantially attenuates the formation of ISVs, which can be rescued by concurrent over-expression of vegfa, indicating that FIH-1/HIF1AN may fine tune VEGF-A signaling.ConclusionsTaken together, our data suggest that FIH-1 interacts with Mib E3 Ubiquitin ligase and modulates vascular development by attenuating VEGF-A signaling activity.

Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish

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Spatiotemporal expression and transcriptional regulation of heme oxygenase and biliverdin reductase genes in zebrafish (Danio rerio) suggest novel roles during early developmental periods of heightened oxidative stress

“…The two paralogs of Nrf2 in zebrafish resulting from the teleost-specific genome duplication event have undergone subfunction partitioning, with Nrf2a thought to act primarily as a transcriptional activator and Nrf2b acting as a transcriptional repressor (Timme-Laragy et al, 2012). Since Nrf2a has been demonstrated to positively regulate hmox1a (Fuse et al, 2015; Nakajima et al, 2011; So et al, 2014) and bvrb in response to Cd exposure (Holowiecki et al, 2016) , we sought to determine its putative role in regulating hmox1a , bvra and bvrb during the early stages hematopoiesis. There was no substantial decrease in bvra or bvrb expression within primitive erythrocytes or hematopoietic tissues in Nrf2a morphants (Figures 3 and 5).…”

Endothelial‐to‐hematopoietic transition: Notch‐ing vessels into blood

“…Subsequent conditional loss‐of‐function experiments in murine VE‐cadherin–expressing ECs confirmed an essential role for Hif1α in HE specification and HSC production . Interestingly, while not yet connected to Notch during blood development, Hif1α was previously linked to the Notch pathway in vascular cells and a subset of cancer cells . Molecularly, Hif1α regulated Mindbomb, an E3 ubiquitin ligase essential for Notch activity, and was suggested to suppress Notch2 .…”

“…Interestingly, while not yet connected to Notch during blood development, Hif1α was previously linked to the Notch pathway in vascular cells and a subset of cancer cells . Molecularly, Hif1α regulated Mindbomb, an E3 ubiquitin ligase essential for Notch activity, and was suggested to suppress Notch2 . Moreover, ROS have been implicated in the regulation of Notch levels, suggesting further work in this area will reveal novel regulatory connections.…”