Noncanonical function of threonyl-tRNA synthetase regulates vascular development in zebrafish

• Tars was identified as a vascular regulator.
• Noncanonical function of tars regulates angiogenesis by mediating Vegf signaling.
• It is conserved that tars regulates angiogenesis between zebrafish and human.

The canonical functions of Aminoacyl-tRNA synthetases (AARSs) are indispensable for protein synthesis. However, recent evidence indicates that some AARSs possess additional biological functions (noncanonical functions) related to immune responses and vascular development. Here, we identified a zebrafish cq16 mutant presenting the disorganized vessels with abnormal branching of the established intersegmental vessels (ISVs) as well as aberrant patterning of the brain vascular network after 50 h post fertilization. The cq16 mutant gene is responsible for encoding threonyl-tRNA synthetase (tars) with a missense mutation. The abnormal branching of ISVs was caused by the increased expression of vascular endothelial growth factor A (vegfa) in tarscq16 mutant. Inhibition of Vegf signaling suppresses the abnormal vascular branching observed in tarscq16 mutant. Furthermore, injection of human TARS mRNA potently reduced the vascular aberrant branching in tarscq16 mutant, indicating a conserved function of tars in regulating angiogenesis between zebrafish and human. Therefore, we conclude that noncanonical function of tars regulates vascular development presumably by modulating the expression of vegfa.