Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins
Vascular morphogenesis requires a delicate gradient of Notch signaling that is controlled, at least in part, by the distribution of ligands (Dll4 and Jagged1). How jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here we showed that Jag1 mRNA is a direct target of zinc finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we found robustly induced by VEGF. Endothelial cells lacking ZFP36 displayed high levels of JAG1 and increased angiogenic sprouting in vitro. Similarly, mice lackingZfp36in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front altered NOTCH1 signaling, increasing the number of tip cells; a phenotype that was rescued by imposing haploinsufficiency ofJag1. Our findings reveal an important feedforward loop, whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis. Overall design: Comparative gene expression profiling analysis from RNA seq of HUVECs (3 biological replicates with 2 technical replicates each) pretreated with DMSO or ZM323 before stimulation with or without VEGF for 1h