GSE130193
Angiogenesis induced by aminoacyl-tRNA synthetase deficiency is dependent on AAR but not UPR pathways
The amino acid response (AAR) and the unfolded protein response (UPR) pathways are closely interconnected and both implicated in regulation of stress-induced angiogenesis. Two kinases, Gcn2 and Perk, transduce signals from AAR and UPR, respectively, and phosphorylate the common target, eIF2alpha, the key regulator of protein translation. However, this interconnection makes it difficult to specify different contributions of AAR and UPR to angiogenesis. In this study, we generated a zebrafish angiogenic model harboring a loss-of-function mutation in the threonyl-tRNA synthetase (tars) gene. While previous studies approximately implicated both AAR and UPR into the angiogenic phenotypes, our gene expression profiling of the tars-/- and sibling embryos, as well as those with knockdown of either Gcn2 or Perk in both genotypes, reveal that only AAR is activated by the tars-deficiency. Phenotypic validations using genetic and pharmacological interference with AAR and UPR confirm that AAR, but not UPR, is required for the tars-deficiency-induced angiogenesis. Thus, this study demonstrates that the closely interconnected AAR and UPR can be independently activated and differentially regulate angiogenesis, which reflects the specificity and efficiency of multiple stress response pathways that are evolved integrally to benefit the organism by ensuring sensing and responding precisely to different types of stress. Overall design: The six samples, including uninjected WT or tars-/- embryos, as well as those with either perk MO or gcn2 MO injected embryos in both genotypes, were subjected to RNA-seq analysis.